TWI693221B - Hydroxyalkyl-piperazine derivatives as cxcr3 receptor modulators - Google Patents

Abstract

The invention relates to compounds of Formula (I)

wherein n, X, R¹ and R² are as described in the description; to pharmaceutically acceptable salts thereof, and to the use of such compounds as medicaments, especially as modulators of the CXCR3 receptor.

Description

Hydroxyalkyl hexahydropyridine derivatives as CXCR3 receptor modulators

衍生物，及其作為藥劑之用途。本發明亦係關於相關態樣，包括用於製備化合物、含有一或多種式(I)化合物之醫藥組合物之方法，及尤其地其作為CXCR3受體調節劑之用途。 The present invention relates to a novel hydroxyalkyl hexahydropyridine of formula (I)

Derivatives, and their use as medicaments. The invention also relates to related aspects, including methods for preparing compounds, pharmaceutical compositions containing one or more compounds of formula (I), and in particular their use as CXCR3 receptor modulators.

Chemokine receptors are a group of G-protein coupled receptors (GPCRs) that bind peptide chemotaxis cytokine ligands with high affinity. The main function of chemokine receptors is to guide white blood cells to lymphoid organs and tissues under resting conditions and during inflammation, but the effects of certain chemokine receptors on non-hematopoietic cells and their progenitor cells have also been identified. .

Chemokine receptor CXCR3 is a G-protein coupled receptor that binds to the inflamed chemokine CXCL9 (originally called MIG, a mononuclear hormone induced by interferon-γ [INF-γ]), CXCL10 (IP-10, INF-γ-inducible protein 10) and CXCL11 (I-TAC, INF-γ-inducible T cell alpha chemoattractant). CXCR3 is mainly expressed on activated T helper type 1 (Th1) lymphocytes, but it also exists on natural killer cells, macrophages, dendritic cells and a small class of B lymphocytes. The three CXCR3 ligands are mainly expressed under inflammatory conditions, and the performance in healthy tissues is extremely low. Cells that can express CXCR3 ligands, for example after exposure to inflammatory cytokines (such as interferon-γ or TNF-α), include different stromal cells, such as endothelial cells, fibroblasts, epithelial cells, keratinocytes but also include Hematopoietic cells, such as macrophages and monocytes. CXCR3 and its ligand (hereinafter referred to as CXCR3 axis) interaction involves guiding the receptor-bearing cells to specific locations in the body, specifically to the sites of inflammation, immune injury and immune dysfunction, and also to tissue damage, apoptosis, cell growth, and blood vessels The induction of stagnation is related. CXCR3 and its ligands are up-regulated and highly expressed in different pathological conditions including autoimmune disorders, inflammation, infection, transplant rejection, fibrosis, neurodegeneration, and cancer.

The role of the CXCR3 axis in autoimmune disorders is confirmed by several preclinical and clinical observations. Histological analysis of the patient's inflammatory lesions or serum levels reveals that autoimmune disorders with high CXCR3 ligand levels or an increased number of CXCR3 positive cells include rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Lupus nephritis, multiple sclerosis (MS), inflammatory bowel disease (IBD; including Crohn's disease and ulcerative colitis) and type I diabetes (Groom, JR and Luster, ADImmunol Cell Biol 2011 , 89,207; Groom, JR and Luster, ADExp Cell Res 2011,317,620; Lacotte, S., Brun, S., Muller, S. and Dumortier, H. Ann NY Acad Sci 2009, 1173, 310). Because the performance of CXCR3 ligands in healthy tissues is extremely low, the relevant evidence cited above strongly suggests the role of CXCR3 in human autoimmune diseases.

Preclinical disease models using CXCR3 deficient mice that lack a CXCR3 ligand or using antibodies that block the function of CXCR3 or one of its ligands further confirm the role of the CXCR3 axis in immunopathology. For example, mice that have been shown to lack CXCR3 or CXCR3 ligand CXCL9 exhibit reduced lesions in a model used for lupus nephritis (Menke, J. et al. J Am Soc Nephrol 2008, 19, 1177). In an animal model used for another form of renal inflammation-interstitial cystitis-, administration of antibodies that block the function of CXCL10 exhibited reduced cyclophosphamide-induced cystitis lesions (Sakthivel, SK et al. J Immune Based Ther Vaccines 2008, 6, 6). Similarly, blocking CXCL10 with antibodies reduced lesions in a rat model of rheumatoid arthritis (Mohan, K. and Issekutz, T.B. J Immunol 2007, 179, 8463). Similarly, in a murine model of inflammatory bowel disease, blocking antibodies against CXCL10 can prevent pathological changes (Singh, U.P. et al. J Interferon Cytokine Res 2008, 28, 31). In addition, experiments conducted using tissues from CXCR3-deficient mice have shown the role of CXCR3 in celiac disease, another autoimmune disorder (Lammers, K.M. et al. Gastroenterology 2008, 135, 194).

Inflammatory diseases associated with higher performance of the CXCR3 axis include chronic obstructive pulmonary disease (COPD), asthma, sarcomatosis, atherosclerosis, and myocarditis (Groom, JR and Luster, ADImmunol Cell Biol 2011, 89, 207; Groom , JR and Luster, ADExp Cell Res 2011,317,620).

A study has shown that CXCR3 positive cells are increased in the lungs of smokers with COPD compared to healthy individuals, and there is immunoreactivity against CXCR3-ligand CXCL10 in bronchial epithelial cells of smokers with COPD , But not in the bronchial epithelial cells of smoked and non-smoked individuals (Saetta, M. et al. Am J Respir Crit Care Med 2002, 165, 1404). These results suggest that the CXCR3 axis may be involved in the recruitment of immune cells in the outer trachea of smokers with COPD. Consistent with these observations, preclinical studies of COPD revealed the reduction of smoke-induced acute pneumonia in CXCR3-deficient mice (Nie, L. et al. Respir Res 2008, 9, 82).

In an atherosclerosis study, CXCR3 expression was found on T cells in human atherosclerotic lesions. Observed in the vascular wall lesions during atherogenesis, CXCR3 ligands CXCL9, CXCL10 and CXCL11 were found in the endothelial and smooth muscle cells related to their lesions, indicating that they involved CXCR3 positive cells, specific activation T Recruitment and retention of lymphocytes (Mach, F. et al. J Clin Invest 1999, 104, 1041).

Preclinical studies further support the role of CXCR3 in the development of atherosclerosis. Deletion of the CXCR3 gene in mice without ApoE results in a significant reduction in the abdominal aorta Development of atherosclerotic lesions (Veillard, N.R. et al. Circulation 2005, 112,870).

The key role of the CXCR3 axis has also been shown in rejection after organ transplantation and bone marrow transplantation-related toxicity (Groom, J.R. and Luster, A.D. Exp Cell Res 2011, 317,620). Pre-clinically, CXCR3-deficient mice exhibited significant resistance to allograft rejection (Hancock, W.W. et al. J Exp Med 2000, 192, 1515).

The plasma concentration of CXCR3 ligand is also positively correlated with different liver diseases including cirrhosis and fibrosis in humans (Tacke, F., et al. Liver Int 2011, 31,840).

In the field of oncology, blocking the CXCR3 axis has been proposed to help limit the metastasis and spread of cancer cells. For example, administration of the small molecule CXCR3 receptor antagonist AMG487 can limit tumor cell cancer metastasis to the lung (Pradelli, E. et al. Int J Cancer 2009, 125, 2586). Functional signs of the role of CXCR3 in regulating B-cell chronic lymphocytic leukemia (CLL) are reported by Trentin and colleagues (Trentin, L. et al. J Clin Invest 1999, 104, 115).

In the central nervous system, blocking the CXCR3 axis can have beneficial effects and prevent neurodegeneration. The increased performance of CXCL10 in the CNS has been shown in ischemia, Alzheimer's disease, multiple sclerosis (MS), and human immunodeficiency virus (HIV)-encephalitis. For example, in vitro experiments show that tissues derived from CXCR3 or CXCL10-deficient mice have reduced neuronal cell death after neurotoxic NMDA treatment when compared to tissues derived from wild-type mice (van Weering, HR, etc. People Hippocampus 2011,21,220). In studies seeking to identify drug-like molecules that provide neuroprotection against HTT fragment-induced neurodegeneration in models used in Huntington's disease, two CXCR3 receptor antagonists were identified (Reinhart, PH et al. Neurobiol Dis 2011,43,248.).

4-thiazolyl-piperidine derivatives as CXCR3 receptor modulators have been disclosed in WO 2007/064553 and WO 2007/070433.

-1-基)-2-雜芳基-乙酮衍生物(A.Prokopowicz等人,Optimization of a biaryl series of CXCR3 antagonists,第244屆美國化學會年會(244^th ACS National Meeting),Philadelphia,US,2012年8月19-23日)。 It has been disclosed in WO 2007/100610, WO 2010/126811, WO 2013/114332, WO 2015/011099, WO 2015/145322 and announcement display that different 1-(hexahydropyridine

L-yl) -2-heteroaryl-yl - ethanone derivative (A.Prokopowicz et al., Optimization of a biaryl series of CXCR3 antagonists, 244 th American Chemical Society ^{(244 th ACS National Meeting),} Philadelphia, US, August 19-23, 2012).

衍生物為強效CXCR3調節劑，其可適用於治療經由CXCR3軸介導或持續之疾病，包括自體免疫病症(例如，類風濕性關節炎、多發性硬化、發炎性腸道疾病、全身性紅斑性狼瘡症、狼瘡腎炎、間質性膀胱炎、乳糜瀉)、發炎病症(例如，哮喘、COPD、動脈粥樣硬化、心肌炎、類肉瘤病)、移植排斥反應、纖維化(例如肝硬化)、神經退化及涉及神經元死亡之病狀(例如，阿茲海默氏病、亨廷頓氏病)及癌症。 The hydroxyalkyl hexahydropyridine of formula (I) has now been found

Derivatives are potent CXCR3 modulators, which are suitable for the treatment of diseases mediated or sustained via the CXCR3 axis, including autoimmune disorders (eg, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, systemic Lupus erythematosus, lupus nephritis, interstitial cystitis, celiac disease), inflammatory conditions (eg, asthma, COPD, atherosclerosis, myocarditis, sarcomatosis), transplant rejection, fibrosis (eg, cirrhosis) , Neurodegenerative and pathological conditions involving neuronal death (eg, Alzheimer's disease, Huntington's disease) and cancer.

1) In the first embodiment, the present invention relates to the compound of formula (I)

Where n represents integer 1 or 2; X represents N or CH; R ¹ represents heteroaryl, wherein heteroaryl is a heteroatom containing 1, 2 or 3 independently selected from oxygen, nitrogen and sulfur (preferably nitrogen) Of 5 to 10 membered monocyclic or bicyclic aromatic rings, and wherein the heteroaryl group is independently unsubstituted or monosubstituted or disubstituted, wherein the substituent is independently selected from the group consisting of: (C _1-4 ) alkane Group; (C _3-6 ) cycloalkyl; (C _1-4 ) alkoxy; (C _1-2 ) alkoxy-(C _1-2 ) alkyl; (C _1-2 ) alkyl- Carbonyl; hydroxy-(C _1-4 ) alkyl; halogen; (C _1-2 ) fluoroalkyl; phenyl; and heteroaryl, wherein the heteroaryl contains 1, 2, or 3 independently selected 5 or 6-membered monocyclic aromatic rings of heteroatoms of oxygen, nitrogen and sulfur (preferably oxygen and nitrogen), and wherein the heteroaryl group is independently unsubstituted or monosubstituted by (C _1-4 ) alkyl; And R ² represents (C _3-6 ) cycloalkyl, (C _1-4 ) alkoxy or (C _1-2 ) fluoroalkyl; and the salts of these compounds (details are pharmaceutically acceptable Salt).

Unless the definitions clearly stated otherwise provide broader or narrower definitions, in the scope of the specification and patent application, the definitions provided herein are intended to be consistently applied as defined in any one of Examples 1) to 24) Compounds of formula (I), (I _TA ), (I _St1 ) and (I _St2 ), with necessary modifications in details . It is understood that the definition or preferred definition of a term is independently defined (and combined with) any definition or preferred definition of any or all other terms as defined herein and may replace each term.

The compound of formula (I) as defined in any one of embodiments 1) to 24) may contain one or more stereogenic centers or asymmetric centers, such as one or more asymmetric carbon atoms. The compound of formula (I) may therefore exist as a mixture of stereoisomers or as a stereoisomerically enriched form, preferably as pure stereoisomers. The mixture of stereoisomers can be separated in a manner known to those skilled in the art.

The term "enriched" (for example when used in the context of enantiomers) is understood in the context of the present invention to mean in particular that the individual enantiomers are at least at least about each other enantiomer. The ratio of 70:30 (necessary modification in details: purity), and especially at least 90:10 (necessary modification in details: 70%/90% purity) exists. Preferably, the term refers to the substantially pure individual enantiomers. The term "substantially" (for example when used in terms such as "substantially pure") is understood in the context of the present invention to mean in particular individual stereoisomers/compositions/compounds etc. Pure stereoisomers/compositions/compounds, etc. are present in an amount of at least 90%, especially at least 95% and especially at least 99%.

The term "halogen" means fluorine, chlorine, bromine or iodine. If "halogen" is a substituent of "heteroaryl" represented by " R ¹ ", the term "halogen" preferably means fluorine or chlorine, and more preferably fluorine.

The term "alkyl" used alone or in combination refers to a straight or branched saturated hydrocarbon chain containing one to four carbon atoms. The term "(C _xy )alkyl" (x and y are each integers) refers to an alkyl group as defined previously containing x to y carbon atoms. For example, (C _1-4 )alkyl contains one to four carbon atoms. Examples of (C _1-4 )alkyl are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, second butyl and third butyl. Examples of (C _1-3 )alkyl are methyl, ethyl, n-propyl and isopropyl. Examples of (C _1-2 )alkyl are methyl and ethyl. If “(C _xy )alkyl” is a substituent of “heteroaryl” represented by “ R ¹ ”, the term “(C _xy )alkyl” means methyl, ethyl, n-propyl, isopropyl Group, n-butyl, isobutyl, second butyl and third butyl and preferably methyl, ethyl, isopropyl and third butyl. If "(C _xy )alkyl" is a substituent of "heteroaryl" which replaces the basic body of "heteroaryl" represented by " R ¹ "(or if "(C _xy )alkyl" is R ^1A "represents the substituent of "heteroaryl"), the term "(C _xy )alkyl" means methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, Dibutyl and tertiary butyl, and preferably methyl. If R ^1A means "(C _xy )alkyl", the term means methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, second butyl and third butyl; Preferred are methyl, ethyl, isopropyl and tert-butyl; and more preferred are methyl, ethyl and isopropyl. If R ^1B means "(C _xy )alkyl", the term means methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, second butyl and third butyl; Preferred are methyl and ethyl; and more preferred is methyl.

The term "alkoxy" used alone or in combination refers to an alkyl-O- group as previously defined for alkyl. The term "(C _xy )alkoxy" (x and y are each integers) refers to an alkoxy group as defined previously containing x to y carbon atoms. For example, (C _1-4 )alkoxy means a group of the formula (C _1-4 )alkyl-O-, where the term "(C _1-4 )alkyl" has the previously given meaning. Examples of (C _1-4 )alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, second butoxy and third butoxy base. Examples of (C _1-2 )alkoxy are methoxy and ethoxy. If "(C _xy )alkoxy" is a substituent for "heteroaryl" representing " R ¹ ", the term "(C _xy )alkoxy" means methoxy, ethoxy, n-propoxy Group, isopropoxy, n-butoxy, isobutoxy, second butoxy and third butoxy, and preferably methoxy. If R ² means "(C _xy )alkoxy", the term means methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, second butoxy Group and third butoxy group, and preferably ethoxy group.

The term "hydroxy-(C _1-4 )alkyl" used alone or in combination refers to an alkyl group as defined previously containing one to four carbon atoms, in which one hydrogen atom has been replaced by a hydroxyl group. Examples of such groups are hydroxy-methyl, 1-hydroxy-ethyl, 2-hydroxy-ethyl, 1-hydroxy-prop-1-yl, 2-hydroxy-prop-1-yl, 3-hydroxy- Prop-1-yl, 1-hydroxy-prop-2-yl, 2-hydroxy-prop-2-yl, 1-hydroxy-but-1-yl, 2-hydroxy-but-1-yl, 3-hydroxy- Butan-1-yl, 4-hydroxy-but-1-yl, 1-hydroxy-but-2-yl, 2-hydroxy-but-2-yl, 3-hydroxy-but-2-yl, 4-hydroxy- Butan-2-yl, 1-hydroxy-2-methyl-prop-1-yl, 2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy-2-methyl-prop-1-yl And 2-hydroxy-1,1-dimethyl-ethyl-1-yl. If "hydroxy-(C _1-4 )alkyl" is a substituent for "heteroaryl" indicating " R ¹ " (or if " R ^1A " indicates "hydroxy-(C _1-4 ) alkyl"), The term "hydroxy-(C _1-4 )alkyl" means hydroxy-methyl, 1-hydroxy-ethyl, 2-hydroxy-ethyl, 1-hydroxy-prop-1-yl, 2-hydroxy-propyl -1-yl, 3-hydroxy-prop-1-yl, 1-hydroxy-prop-2-yl, 2-hydroxy-prop-2-yl, 1-hydroxy-but-1-yl, 2-hydroxy-butan -1-yl, 3-hydroxy-but-1-yl, 4-hydroxy-but-1-yl, 1-hydroxy-but-2-yl, 2-hydroxy-but-2-yl, 3-hydroxy-butan -2-yl, 4-hydroxy-but-2-yl, 1-hydroxy-2-methyl-prop-1-yl, 2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy-2 -Methyl-prop-1-yl and 2-hydroxy-1,1-dimethyl-ethyl-1-yl. Hydroxy-methyl and 1-hydroxy-ethyl are preferred and 1-hydroxy-ethyl is more preferred.

The term "(C _xa-ya )alkoxy-(C _xy )alkyl" (x, xa, y, and ya are each integers) refers to an alkyl group as defined previously containing x to y carbon atoms, wherein One hydrogen atom already contains xa to ya carbon atoms and is replaced by an alkoxy group as defined previously (C _xa-ya ). For example, "(C _1-2 )alkoxy-(C _1-2 )alkyl" refers to a (C _1-2 )alkyl group as defined previously containing one or two carbon atoms, one of which The hydrogen atom already contains one or two carbon atoms and is replaced by a (C _1-2 ) alkoxy group as previously defined. Examples of (C _1-2 )alkoxy-(C _1-2 )alkyl are methoxy-methyl, 1-methoxy-ethyl, 2-methoxy-ethyl, ethoxy- Methyl, 1-ethoxy-ethyl and 2-ethoxy-ethyl. If "(C _1-2 )alkoxy-(C _1-2 )alkyl" is a substituent of "heteroaryl" indicating " R ¹ " (or if " R ^1A " indicates "(C _1-2 )Alkoxy-(C _1-2 )alkyl”), the term “(C _1-2 )alkoxy-(C _1-2 )alkyl” means methoxy-methyl, 1-methyl Oxy-ethyl, 2-methoxy-ethyl, ethoxy-methyl, 1-ethoxy-ethyl and 2-ethoxy-ethyl, and preferably methoxy-methyl .

The term "fluoroalkyl" refers to an alkyl group as defined previously containing one or two carbon atoms in which one or more (and possibly all) hydrogen atoms have been replaced with fluorine. The term "(C _xy )fluoroalkyl" (x and y are each integers) refers to a fluoroalkyl group as defined previously containing x to y carbon atoms. For example, (C _1-2 )fluoroalkyl contains one or two carbon atoms, of which one to five hydrogen atoms have been replaced with fluorine. Representative examples of (C _1-2 )fluoroalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 2-fluoroethyl, 2 , 2-difluoroethyl and 2,2,2-trifluoroethyl. If "(C _xy )fluoroalkyl" is a substituent of "heteroaryl" representing " R ¹ " (or if " R ^1A " represents "(C _xy ) fluoroalkyl"), then the term "(C _xy) )Fluoroalkyl'' preferably means fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 2-fluoroethyl, 2,2-difluoro Ethyl and 2,2,2-trifluoroethyl, and more preferably difluoromethyl and trifluoromethyl. If R ² represents "(C _xy )fluoroalkyl", the term preferably means fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 2 -Fluoroethyl, 2,2-difluoroethyl and 2,2,2-trifluoroethyl, and more preferably trifluoromethyl.

The term "(C _xy )alkyl-carbonyl" (x and y are each integers) refers to an alkyl group as defined previously containing x to y carbon atoms connected to the rest of the molecule via a carbonyl group. For example, the (C _1-2 )alkyl-carbonyl group contains one or two carbon atoms in the alkyl portion and is connected to the rest of the molecule via the carbonyl group. Examples of "(C _1-2 )alkyl-carbonyl" are methyl-carbonyl and ethyl-carbonyl. If "(C _1-2 )alkyl-carbonyl" is a substituent of "heteroaryl" indicating " R ¹ " (or if " R ^1A " indicates "(C _1-2 ) alkyl-carbonyl"), The term "(C _1-2 )alkyl-carbonyl" means methyl-carbonyl and ethyl-carbonyl, and is preferably methyl-carbonyl (acetyl).

The term "cycloalkyl" used alone or in combination refers to a saturated carbocyclic ring containing three to six carbon atoms. The term "(C _xy )cycloalkyl" (x and y are each integers) refers to a cycloalkyl group as defined previously containing x to y carbon atoms. For example, (C _3-6 )cycloalkyl contains three to six carbon atoms. Examples of (C _3-6 )cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. If "(C _3-6 )cycloalkyl" is a substituent for "heteroaryl" meaning " R ¹ " (or if " R ^1A " means "(C _3-6 ) cycloalkyl"), then the term "(C _3-6 )cycloalkyl" means cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, preferably cyclopropyl and cyclobutyl and more preferably cyclopropyl. If “ R ² ”means “(C _3-6 )cycloalkyl”, the term means cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl and preferably cyclopropyl.

啶基、

啉基、喹唑啉基、喹喏啉基、酞嗪基、吡咯并吡啶基、吡唑并吡啶基及咪唑并吡啶基。在雜芳基具有更受限之定義之情況下，實例之清單可藉由考慮各別限制自前述清單解釋。舉例而言，「雜芳基，其中雜芳基為含有1、2或3個獨立地選自氧、氮及硫之雜原子之5或6員單環芳族環」之實例為呋喃基、噁唑基、異噁唑基、噁二唑基、噻吩基、噻唑 基、異噻唑基、噻二唑基、吡咯基、咪唑基、吡唑基、三唑基、吡啶基、嘧啶基、噠嗪基、吡嗪基及三嗪基。表示「R ¹ 」之「雜芳基」之較佳實例為吡唑基(尤其吡唑-1-基)、三唑基(尤其[1,2,4]三唑-1-基)、吲哚基(尤其吲哚-1-基)、苯并咪唑基(尤其苯并咪唑-1-基)及咪唑并[4,5-b]吡啶基(尤其咪唑并[4,5-b]吡啶-3-基)，且最佳為[1,2,4]三唑-1-基；雜芳基可如所特定定義未經取代或經取代；表示「R ¹ 」之「未經取代或經取代之雜芳基」之較佳實例為3-甲基-吡唑-1-基、3-甲基-[1,2,4]三唑-1-基、3-乙基-[1,2,4]三唑-1-基、3-異丙基-[1,2,4]三唑-1-基、3-第三丁基-[1,2,4]三唑-1-基、3-環丙基-[1,2,4]三唑-1-基、3-環丁基-[1,2,4]三唑-1-基、3-甲氧基甲基-[1,2,4]三唑-1-基、3-乙醯基-[1,2,4]三唑-1-基、3-(1-羥基-乙基)-[1,2,4]三唑-1-基、3-二氟甲基-[1,2,4]三唑-1-基、3-三氟甲基-[1,2,4]三唑-1-基、3-苯基-[1,2,4]三唑-1-基、3-(5-甲基-[1,2,4]噁二唑-3-基)-[1,2,4]三唑-1-基、3-(吡啶-2-基)-[1,2,4]三唑-1-基、5-甲基-[1,2,4]三唑-1-基、5-乙基-[1,2,4]三唑-1-基、3,5-二甲基-[1,2,4]三唑-1-基、3-乙基-5-甲基-[1,2,4]三唑-1-基、5-乙基-3-甲基-[1,2,4]三唑-1-基、5-甲氧基-吲哚-1-基、5-氟-吲哚-1-基、苯并咪唑-1-基及咪唑并[4,5-b]吡啶-3-基。其他實例為3-乙基-吡唑-1-基及3-環丙基-吡唑-1-基。為表示「R ¹ 」之雜芳基之取代基的「雜芳基」(或表示「R ^1A 」之「雜芳基」)之較佳實例為噁二唑基(尤其[1,2,4]噁二唑-3-基)及吡啶基(尤其吡啶-2-基)；雜芳基可如所特定定義未經取代或經取代；為表示「R ¹ 」之雜芳基之取代基的「未經取代或經取代之雜芳基」(或表示「R ^1A 」之「未經取代或經取代之雜芳基」)之較佳實例為5-甲基-[1,2,4]噁二唑-3-基及吡啶-2-基。 The term "heteroaryl" used alone or in combination refers to a heteroaryl group as defined specifically which may be unsubstituted or substituted as specified. "Heteroaryl, wherein heteroaryl is a 5- to 10-membered monocyclic or bicyclic aromatic ring containing 1, 2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulfur" Examples of furyl and oxazole Group, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl , Pyrazinyl, triazinyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzoxazolyl, benzene Isoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, benzoxadiazolyl, benzothiadiazolyl, quinolinyl, isoquinolinyl,

Pyridyl,

Porphyrinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrrolopyridinyl, pyrazolopyridinyl and imidazopyridinyl. In the case where the heteroaryl group has a more restricted definition, the list of examples can be explained from the foregoing list by considering various restrictions. For example, "heteroaryl, wherein heteroaryl is a 5 or 6 membered monocyclic aromatic ring containing 1, 2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulfur" Examples of furanyl, Oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, pyridyl Azinyl, pyrazinyl and triazinyl. Preferred examples of "heteroaryl" representing " R ¹ "are pyrazolyl (especially pyrazol-1-yl), triazolyl (especially [1,2,4]triazol-1-yl), indole Indolyl (especially indol-1-yl), benzimidazolyl (especially benzimidazol-1-yl) and imidazo[4,5-b]pyridyl (especially imidazo[4,5-b]pyridine -3-yl), and preferably [1,2,4]triazol-1-yl; heteroaryl may be unsubstituted or substituted as specifically defined; means "unsubstituted or" for " R ¹ " Preferred examples of "substituted heteroaryl" are 3-methyl-pyrazol-1-yl, 3-methyl-[1,2,4]triazol-1-yl, 3-ethyl-[1 ,2,4]triazol-1-yl, 3-isopropyl-[1,2,4]triazol-1-yl, 3-tert-butyl-[1,2,4]triazole-1 -Yl, 3-cyclopropyl-[1,2,4]triazol-1-yl, 3-cyclobutyl-[1,2,4]triazol-1-yl, 3-methoxymethyl -[1,2,4]triazol-1-yl, 3-acetoyl-[1,2,4]triazol-1-yl, 3-(1-hydroxy-ethyl)-[1,2 ,4]triazol-1-yl, 3-difluoromethyl-[1,2,4]triazol-1-yl, 3-trifluoromethyl-[1,2,4]triazol-1- Group, 3-phenyl-[1,2,4]triazol-1-yl, 3-(5-methyl-[1,2,4]oxadiazol-3-yl)-[1,2, 4]Triazol-1-yl, 3-(pyridin-2-yl)-[1,2,4]triazol-1-yl, 5-methyl-[1,2,4]triazole-1- Group, 5-ethyl-[1,2,4]triazol-1-yl, 3,5-dimethyl-[1,2,4]triazol-1-yl, 3-ethyl-5- Methyl-[1,2,4]triazol-1-yl, 5-ethyl-3-methyl-[1,2,4]triazol-1-yl, 5-methoxy-indole- 1-yl, 5-fluoro-indol-1-yl, benzimidazol-1-yl and imidazo[4,5-b]pyridin-3-yl. Other examples are 3-ethyl-pyrazol-1-yl and 3-cyclopropyl-pyrazol-1-yl. Is a "R ^1" of the heteroaryl group substituted with an aryl group of "heteroaryl" (on or "R ^1A", "heteroaryl" of) Examples of preferred oxadiazolyl (especially [1,2,4 ] Oxadiazol-3-yl) and pyridyl (especially pyrid-2-yl); heteroaryl may be unsubstituted or substituted as specifically defined; is a substituent for heteroaryl representing " R ¹ " A preferred example of "unsubstituted or substituted heteroaryl" (or "unsubstituted or substituted heteroaryl" meaning " R ^1A ") is 5-methyl-[1,2,4] Oxadiazol-3-yl and pyridin-2-yl.

2) Another embodiment of the present invention relates to the compound of formula (I) as in embodiment 1), wherein n represents an integer of 1 or 2; X represents N; R ¹ represents a heteroaryl group, wherein the heteroaryl group contains 1, 5 to 10 membered monocyclic or bicyclic aromatic rings of 2 or 3 nitrogen atoms, and wherein the heteroaryl group is independently unsubstituted or monosubstituted or disubstituted, wherein the substituent is independently selected from the group consisting of: ( C _1-4 ) alkyl; (C _3-6 ) cycloalkyl; (C _1-4 ) alkoxy; (C _1-2 ) alkoxy-(C _1-2 ) alkyl; (C _{1 -2} ) alkyl-carbonyl; hydroxy-(C _1-4 ) alkyl; halogen; and (C _1-2 ) fluoroalkyl; and R ² represents (C _3-6 ) cycloalkyl, (C _{1- 4} ) Alkoxy or (C _1-2 )fluoroalkyl; and salts of these compounds (detailed pharmaceutically acceptable salts).

3) Another embodiment of the present invention relates to a compound of formula (I) as in embodiment 1), wherein n represents an integer of 1 or 2; X represents N; R ¹ represents a mono- or di-substituted independently containing 2 or 5-membered monocyclic heteroaryl of 3 nitrogen atoms, wherein the substituents are independently selected from the group consisting of (C _1-4 ) alkyl, (C _3-6 ) cycloalkyl, (C _1-2 ) Alkoxy-(C _1-2 )alkyl, hydroxy-(C _1-4 )alkyl and (C _1-2 )fluoroalkyl; or unsubstituted or substituted by (C _1-4 )alkoxy or A halogen-substituted 9-membered bicyclic aromatic ring containing 1, 2 or 3 nitrogen atoms; and R ² represents (C _3-6 )cycloalkyl, (C _1-4 )alkoxy or trifluoromethyl; And salts of these compounds (detailed pharmacologically acceptable salts).

4) Another embodiment of the present invention relates to compounds of formula (I) according to any one of embodiments 1) to 3), wherein n represents an integer of 1; and the salts of these compounds (detailed in medicine Acceptable salt).

5) Another embodiment of the present invention relates to compounds of formula (I) as in any one of embodiments 1) to 3), wherein n represents an integer of 2; and the salts of these compounds (detailed medical Acceptable salt).

6) Another embodiment of the present invention relates to compounds of formula (I) as in any one of embodiments 1) to 5), wherein R ¹ represents independently substituted mono- or di-substituted containing 2 or 3 nitrogen atoms 5 membered monocyclic heteroaryl, wherein the substituents are independently selected from the group consisting of (C _1-4 ) alkyl, (C _3-6 ) cycloalkyl and (C _1-2 ) fluoroalkyl; And salts of these compounds (detailed pharmacologically acceptable salts).

7) Another embodiment of the present invention relates to compounds of formula (I) according to any one of embodiments 1) to 6), wherein R ² represents trifluoromethyl; and salts of these compounds (details Pharmaceutically acceptable salts).

8) Another embodiment of the present invention relates to the compound of formula (I) as in embodiment 1), which is also a compound of formula (I _TA )

Where n represents the integer 1 or 2; R ^1A represents hydrogen, (C _1-4 ) alkyl, (C _3-6 ) cycloalkyl, (C _1-2 ) alkoxy-(C _1-2 ) alkyl , (C _1-2 )alkyl-carbonyl, hydroxy-(C _1-4 )alkyl, (C _1-2 )fluoroalkyl, phenyl or heteroaryl, wherein heteroaryl contains 1, 2 or 3 5 or 6 membered monocyclic aromatic rings independently selected from heteroatoms of oxygen, nitrogen and sulfur (preferably oxygen and nitrogen), and wherein the heteroaryl group is independently unsubstituted or substituted by (C _1-4 ) Alkyl monosubstituted; R ^1B represents hydrogen or (C _1-4 ) alkyl; and R ² represents (C _3-6 ) cycloalkyl, (C _1-4 ) alkoxy or (C _1-2 ) fluorine Alkyl; and salts of these compounds (detailed pharmaceutically acceptable salts).

9) Another embodiment of the present invention relates to a compound of formula (I _TA ) as in embodiment 8), wherein n represents an integer of 1 or 2; R ^1A represents (C _1-4 )alkyl, (C _3-6 ) Cycloalkyl, (C _1-2 )alkoxy-(C _1-2 )alkyl, (C _1-2 )alkyl-carbonyl, hydroxy-(C _1-4 )alkyl or (C _1-2 ) Fluoroalkyl; and R ^1B represents hydrogen or (C _1-4 ) alkyl; or R ^1A represents hydrogen and R ^1B represents (C _1-4 ) alkyl; and R ² represents (C _3-6 ) cycloalkane Group, (C _1-4 ) alkoxy group or (C _1-2 ) fluoroalkyl group; and salts of such compounds (detailed pharmaceutically acceptable salts).

10) Another embodiment of the present invention relates to a compound of formula (I _TA ) as in embodiment 8), wherein n represents an integer of 1 or 2; R ^1A represents (C _1-4 )alkyl or (C _3-6 ) Cycloalkyl; R ^1B represents hydrogen or (C _1-4 ) alkyl; and R ² represents cyclopropyl, ethoxy, or trifluoromethyl; and salts of these compounds (detailed medical Accepted salt).

11) Another embodiment of the present invention relates to compounds of formula (I _TA ) according to any one of embodiments 8) to 10), wherein n represents an integer of 1; and the salts of these compounds (detailed medical science) Acceptable salt).

12) Another embodiment of the present invention relates to compounds of formula (I _TA ) according to any one of embodiments 8) to 10), wherein n represents an integer of 2; and salts of these compounds (details in medicine Acceptable salt).

13) Another embodiment of the present invention relates to a compound of formula (I _TA ) according to any one of embodiments 8), 9), 11) or 12), wherein R ^1A represents (C _1-4 )alkyl, (C _3-6 )cycloalkyl, (C _1-2 )alkoxy-(C1 _-2 )alkyl, hydroxy-(C _1-4 )alkyl or (C _1-2 )fluoroalkyl; and Regarding the salts of these compounds (detailed pharmaceutically acceptable salts).

14) Another embodiment of the present invention relates to a compound of formula (I _TA ) according to any one of embodiments 8), 9), 11) or 12), wherein R ^1A represents (C _1-4 )alkyl or (C _3-6 )cycloalkyl; and salts of these compounds (detailed pharmaceutically acceptable salts).

15) Another embodiment of the present invention relates to a compound of formula (I _TA ) as in any one of embodiments 8) to 12), wherein R ^1A represents methyl, ethyl, isopropyl or cyclopropyl; and Regarding the salts of these compounds (detailed pharmaceutically acceptable salts).

16) Another embodiment of the present invention relates to compounds of formula (I _TA ) as in any one of embodiments 8) to 15), wherein R ^1B represents hydrogen; and salts of these compounds (detailed medical science) Acceptable salt).

17) Another embodiment of the present invention relates to compounds of formula (I _TA ) according to any one of embodiments 8) to 15), wherein R ^1B represents a methyl group; and salts of these compounds (detailed medicine Academically acceptable salt).

18) Another embodiment of the present invention relates to a compound of formula (I _TA ) according to any one of embodiments 8), 9) or 11) to 17), wherein R ² represents (C _1-4 ) alkoxy Or (C _1-2 )fluoroalkyl; and salts of these compounds (detailed pharmaceutically acceptable salts).

19) Another embodiment of the present invention relates to compounds of formula (I _TA ) as in any one of embodiments 8) to 17), wherein R ² represents trifluoromethyl; and salts of these compounds (details Pharmaceutically acceptable salts).

20) Another embodiment of the present invention relates to the compound according to any one of embodiments 1) to 19), wherein the absolute configuration of the _{stereosymmetric} center is as depicted in formula (I _St1 )

And salts of these compounds (detailed pharmacologically acceptable salts).

21) Another embodiment of the present invention relates to the compound according to any one of embodiments 1) to 19), wherein the absolute configuration of the _{stereosymmetric} center is as depicted in formula (I _St2 )

And salts of these compounds (detailed pharmacologically acceptable salts).

-1-基}-乙酮；2-(3,5-二甲基-[1,2,4]三唑-1-基)-1-{(S)-2-羥甲基-4-[2-三氟甲基-4-(2-三氟甲基-嘧啶-5-基)-噻唑-5-基]-六氫吡

-1-基}-乙酮；2-(3-環丙基-[1,2,4]三唑-1-基)-1-{(S)-2-羥甲基-4-[2-三氟甲基-4-(2-三氟甲基-嘧啶-5-基)-噻唑-5-基]-六氫吡

-1-基}-乙酮；1-{(S)-2-羥甲基-4-[2-三氟甲基-4-(2-三氟甲基-嘧啶-5-基)-噻唑-5-基]-六氫吡

-1-基}-2-(3-異丙基-[1,2,4]三唑-1-基)-乙酮；1-{(S)-2-羥甲基-4-[2-三氟甲基-4-(2-三氟甲基-嘧啶-5-基)-噻唑-5-基]-六氫吡

-1-基}-2-(3-三氟甲基-[1,2,4]三唑-1-基)-乙酮；1-{(S)-4-[4-(2-乙氧基-嘧啶-5-基)-2-三氟甲基-噻唑-5-基]-2-羥甲基-六氫吡

-1-基}-2-(3-三氟甲基-[1,2,4]三唑-1-基)-乙酮；2-(3,5-二甲基-[1,2,4]三唑-1-基)-1-{(S)-4-[4-(2-乙氧基-嘧啶-5-基)-2-三氟甲基-噻唑-5-基]-2-羥甲基-六氫吡

-1-基}-乙酮；1-{(S)-4-[4-(2-環丙基-嘧啶-5-基)-2-三氟甲基-噻唑-5-基]-2-羥甲基-六氫吡

-1-基}-2-(3,5-二甲基-[1,2,4]三唑-1-基)-乙酮；1-{(S)-4-[4-(2-環丙基-嘧啶-5-基)-2-三氟甲基-噻唑-5-基]-2-羥甲基-六氫吡

-1-基}-2-(3-三氟甲基-[1,2,4]三唑-1-基)-乙酮；1-{(R)-2-羥甲基-4-[2-三氟甲基-4-(6-三氟甲基-吡啶-3-基)-噻唑-5-基]-六氫吡

-1-基}-2-(3-異丙基-[1,2,4]三唑-1-基)-乙酮；1-{(R)-2-羥甲基-4-[2-三氟甲基-4-(2-三氟甲基-嘧啶-5-基)-噻唑-5-基]-六氫吡

-1-基}-2-(3-異丙基-[1,2,4]三唑-1-基)-乙酮；2-(3,5-二甲基-[1,2,4]三唑-1-基)-1-{(R)-2-羥甲基-4-[2-三氟甲基-4-(2-三氟甲基-嘧啶-5-基)-噻唑-5-基]-六氫吡

-1-基}-乙酮；2-苯并咪唑-1-基-1-{(R)-2-羥甲基-4-[2-三氟甲基-4-(2-三氟甲基-嘧啶-5-基)-噻唑-5-基]-六氫吡

-1-基}-乙酮； 2-(5-氟-吲哚-1-基)-1-{(R)-2-羥甲基-4-[2-三氟甲基-4-(2-三氟甲基-嘧啶-5-基)-噻唑-5-基]-六氫吡

-1-基}-乙酮；1-{(R)-2-羥甲基-4-[2-三氟甲基-4-(2-三氟甲基-嘧啶-5-基)-噻唑-5-基]-六氫吡

-1-基}-2-(5-甲氧基-吲哚-1-基)-乙酮；1-{(R)-2-羥甲基-4-[2-三氟甲基-4-(2-三氟甲基-嘧啶-5-基)-噻唑-5-基]-六氫吡

-1-基}-2-(3-甲基-[1,2,4]三唑-1-基)-乙酮；1-{(R)-2-羥甲基-4-[2-三氟甲基-4-(2-三氟甲基-嘧啶-5-基)-噻唑-5-基]-六氫吡

-1-基}-2-(3-甲氧基甲基-[1,2,4]三唑-1-基)-乙酮；1-{(R)-2-羥甲基-4-[2-三氟甲基-4-(2-三氟甲基-嘧啶-5-基)-噻唑-5-基]-六氫吡

-1-基}-2-[3-(5-甲基-[1,2,4]噁二唑-3-基)-[1,2,4]三唑-1-基]-乙酮；1-{(R)-2-羥甲基-4-[2-三氟甲基-4-(2-三氟甲基-嘧啶-5-基)-噻唑-5-基]-六氫吡

-1-基}-2-(3-苯基-[1,2,4]三唑-1-基)-乙酮；2-(3-乙醯基-[1,2,4]三唑-1-基)-1-{(R)-2-羥甲基-4-[2-三氟甲基-4-(2-三氟甲基-嘧啶-5-基)-噻唑-5-基]-六氫吡

-1-基}-乙酮；2-[3-(1-羥基-乙基)-[1,2,4]三唑-1-基]-1-{(R)-2-羥甲基-4-[2-三氟甲基-4-(2-三氟甲基-嘧啶-5-基)-噻唑-5-基]-六氫吡

-1-基}-乙酮；1-{(R)-2-羥甲基-4-[2-三氟甲基-4-(2-三氟甲基-嘧啶-5-基)-噻唑-5-基]-六氫吡

-1-基}-2-(3-甲基-吡唑-1-基)-乙酮；1-{(R)-2-羥甲基-4-[2-三氟甲基-4-(2-三氟甲基-嘧啶-5-基)-噻唑-5-基]-六氫吡

-1-基}-2-(3-吡啶-2-基-[1,2,4]三唑-1-基)-乙酮；2-(3-乙基-5-甲基-[1,2,4]三唑-1-基)-1-{(R)-2-羥甲基-4-[2-三氟甲基-4-(2-三氟甲基-嘧啶-5-基)-噻唑-5-基]-六氫吡

-1-基}-乙酮；2-(5-乙基-3-甲基-[1,2,4]三唑-1-基)-1-{(R)-2-羥甲基-4-[2-三氟甲基-4-(2-三氟甲基-嘧啶-5-基)-噻唑-5-基]-六氫吡

-1-基}-乙酮；1-{(R)-2-羥甲基-4-[2-三氟甲基-4-(2-三氟甲基-嘧啶-5-基)-噻唑- 5-基]-六氫吡

-1-基}-2-咪唑并[4,5-b]吡啶-3-基-乙酮；2-(3,5-二甲基-[1,2,4]三唑-1-基)-1-{(R)-2-(2-羥基-乙基)-4-[2-三氟甲基-4-(2-三氟甲基-嘧啶-5-基)-噻唑-5-基]-六氫吡

-1-基}-乙酮；1-{(R)-2-(2-羥基-乙基)-4-[2-三氟甲基-4-(2-三氟甲基-嘧啶-5-基)-噻唑-5-基]-六氫吡

-1-基}-2-(3-三氟甲基-[1,2,4]三唑-1-基)-乙酮；2-(3-環丁基-[1,2,4]三唑-1-基)-1-{(R)-2-(2-羥基-乙基)-4-[2-三氟甲基-4-(2-三氟甲基-嘧啶-5-基)-噻唑-5-基]-六氫吡

-1-基}-乙酮；2-(3-第三丁基-[1,2,4]三唑-1-基)-1-{(R)-2-(2-羥基-乙基)-4-[2-三氟甲基-4-(2-三氟甲基-嘧啶-5-基)-噻唑-5-基]-六氫吡

-1-基}-乙酮；2-(3-環丙基-[1,2,4]三唑-1-基)-1-{(R)-2-(2-羥基-乙基)-4-[2-三氟甲基-4-(2-三氟甲基-嘧啶-5-基)-噻唑-5-基]-六氫吡

-1-基}-乙酮；2-(3-乙基-[1,2,4]三唑-1-基)-1-{(R)-2-(2-羥基-乙基)-4-[2-三氟甲基-4-(2-三氟甲基-嘧啶-5-基)-噻唑-5-基]-六氫吡

-1-基}-乙酮；2-(5-乙基-[1,2,4]三唑-1-基)-1-{(R)-2-(2-羥基-乙基)-4-[2-三氟甲基-4-(2-三氟甲基-嘧啶-5-基)-噻唑-5-基]-六氫吡

-1-基}-乙酮；1-{(R)-2-(2-羥基-乙基)-4-[2-三氟甲基-4-(2-三氟甲基-嘧啶-5-基)-噻唑-5-基]-六氫吡

-1-基}-2-(3-異丙基-[1,2,4]三唑-1-基)-乙酮；1-{(R)-2-(2-羥基-乙基)-4-[2-三氟甲基-4-(2-三氟甲基-嘧啶-5-基)-噻唑-5-基]-六氫吡

-1-基}-2-(3-甲基-[1,2,4]三唑-1-基)-乙酮；1-{(R)-2-(2-羥基-乙基)-4-[2-三氟甲基-4-(2-三氟甲基-嘧啶-5-基)-噻唑-5-基]-六氫吡

-1-基}-2-(5-甲基-[1,2,4]三唑-1-基)-乙酮；1-{(R)-2-(2-羥基-乙基)-4-[2-三氟甲基-4-(2-三氟甲基-嘧啶-5-基)-噻唑-5-基]-六氫吡

-1-基}-2-(3-甲氧基甲基-[1,2,4]三唑-1-基)-乙酮；及2-(3-二氟甲基-[1,2,4]三唑-1-基)-1-{(R)-2-羥甲基-4-[2-三氟甲基-4-(2-三氟甲基-嘧啶-5-基)-噻唑-5-基]-六氫吡

-1-基}-乙酮；或該等化合物之鹽(詳言之醫藥學上可接受之鹽)。 22) Examples of compounds of formula (I) as defined in Example 1) are selected from the group consisting of 2-(3-third-butyl-[1,2,4]triazol-1-yl) -1-{(S)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydro Pyridine

-1-yl}-ethanone; 2-(3,5-dimethyl-[1,2,4]triazol-1-yl)-1-{(S)-2-hydroxymethyl-4- [2-Trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone; 2-(3-cyclopropyl-[1,2,4]triazol-1-yl)-1-{(S)-2-hydroxymethyl-4-[2 -Trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone; 1-{(S)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazole -5-yl]-hexahydropyridine

-1-yl}-2-(3-isopropyl-[1,2,4]triazol-1-yl)-ethanone; 1-{(S)-2-hydroxymethyl-4-[2 -Trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-2-(3-trifluoromethyl-[1,2,4]triazol-1-yl)-ethanone; 1-{(S)-4-[4-(2-ethyl Oxy-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-hydroxymethyl-hexahydropyridine

-1-yl}-2-(3-trifluoromethyl-[1,2,4]triazol-1-yl)-ethanone; 2-(3,5-dimethyl-[1,2, 4]Triazol-1-yl)-1-{(S)-4-[4-(2-ethoxy-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]- 2-hydroxymethyl-hexahydropyridine

-1-yl}-ethanone; 1-{(S)-4-[4-(2-cyclopropyl-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2 -Hydroxymethyl-hexahydropyridine

-1-yl}-2-(3,5-dimethyl-[1,2,4]triazol-1-yl)-ethanone; 1-{(S)-4-[4-(2- Cyclopropyl-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-hydroxymethyl-hexahydropyridine

-1-yl}-2-(3-trifluoromethyl-[1,2,4]triazol-1-yl)-ethanone; 1-{(R)-2-hydroxymethyl-4-[ 2-trifluoromethyl-4-(6-trifluoromethyl-pyridin-3-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-2-(3-isopropyl-[1,2,4]triazol-1-yl)-ethanone; 1-{(R)-2-hydroxymethyl-4-[2 -Trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-2-(3-isopropyl-[1,2,4]triazol-1-yl)-ethanone; 2-(3,5-dimethyl-[1,2,4 ]Triazol-1-yl)-1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazole -5-yl]-hexahydropyridine

-1-yl}-ethanone; 2-benzimidazol-1-yl-1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl -Pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone; 2-(5-fluoro-indol-1-yl)-1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl-4-( 2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone; 1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazole -5-yl]-hexahydropyridine

-1-yl}-2-(5-methoxy-indol-1-yl)-ethanone; 1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl-4 -(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone; 1-{(R)-2-hydroxymethyl-4-[2- Trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-2-(3-methoxymethyl-[1,2,4]triazol-1-yl)-ethanone; 1-{(R)-2-hydroxymethyl-4- [2-Trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-2-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-[1,2,4]triazol-1-yl]-ethanone ; 1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydro Pyridine

-1-yl}-2-(3-phenyl-[1,2,4]triazol-1-yl)-ethanone; 2-(3-acetoxy-[1,2,4]triazole -1-yl)-1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazole-5- Radical]-hexahydropyridine

-1-yl}-ethanone; 2-[3-(1-hydroxy-ethyl)-[1,2,4]triazol-1-yl]-1-{(R)-2-hydroxymethyl -4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone; 1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazole -5-yl]-hexahydropyridine

-1-yl}-2-(3-methyl-pyrazol-1-yl)-ethanone; 1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl-4- (2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-2-(3-pyridin-2-yl-[1,2,4]triazol-1-yl)-ethanone; 2-(3-ethyl-5-methyl-[1 ,2,4]triazol-1-yl)-1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidine-5- Group)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone; 2-(5-ethyl-3-methyl-[1,2,4]triazol-1-yl)-1-{(R)-2-hydroxymethyl- 4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone; 1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazole -5-yl]-hexahydropyridine

-1-yl}-2-imidazo[4,5-b]pyridin-3-yl-ethanone; 2-(3,5-dimethyl-[1,2,4]triazol-1-yl )-1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazole-5 -Yl]-hexahydropyridine

-1-yl}-ethanone; 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidine-5 -Yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-2-(3-trifluoromethyl-[1,2,4]triazol-1-yl)-ethanone; 2-(3-cyclobutyl-[1,2,4] Triazol-1-yl)-1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidine-5- Group)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone; 2-(3-tert-butyl-[1,2,4]triazol-1-yl)-1-{(R)-2-(2-hydroxy-ethyl )-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone; 2-(3-cyclopropyl-[1,2,4]triazol-1-yl)-1-{(R)-2-(2-hydroxy-ethyl) -4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone; 2-(3-ethyl-[1,2,4]triazol-1-yl)-1-{(R)-2-(2-hydroxy-ethyl)- 4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone; 2-(5-ethyl-[1,2,4]triazol-1-yl)-1-{(R)-2-(2-hydroxy-ethyl)- 4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone; 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidine-5 -Yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-2-(3-isopropyl-[1,2,4]triazol-1-yl)-ethanone; 1-{(R)-2-(2-hydroxy-ethyl) -4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone; 1-{(R)-2-(2-hydroxy-ethyl)- 4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-2-(5-methyl-[1,2,4]triazol-1-yl)-ethanone; 1-{(R)-2-(2-hydroxy-ethyl)- 4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-2-(3-methoxymethyl-[1,2,4]triazol-1-yl)-ethanone; and 2-(3-difluoromethyl-[1,2 ,4]triazol-1-yl)-1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl) -Thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone; or salts of these compounds (detailed pharmaceutically acceptable salts).

-1-基}-2-(3-甲基-吡唑-1-基)-乙酮；2-(3-乙基-吡唑-1-基)-1-{(R)-2-(2-羥基-乙基)-4-[2-三氟甲基-4-(2-三氟甲基-嘧啶-5-基)-噻唑-5-基]-六氫吡

-1-基}-乙酮；2-(3-環丙基-吡唑-1-基)-1-{(R)-2-(2-羥基-乙基)-4-[2-三氟甲基-4-(2-三氟甲基-嘧啶-5-基)-噻唑-5-基]-六氫吡

-1-基}-乙酮；1-{(S)-2-羥甲基-4-[2-三氟甲基-4-(2-三氟甲基-嘧啶-5-基)-噻唑-5-基]-六氫吡

-1-基}-2-(3-甲基-吡唑-1-基)-乙酮；2-(3-乙基-吡唑-1-基)-1-{(S)-2-羥甲基-4-[2-三氟甲基-4-(2-三氟甲基-嘧啶-5-基)-噻唑-5-基]-六氫吡

-1-基}-乙酮；及2-(3-環丙基-吡唑-1-基)-1-{(S)-2-羥甲基-4-[2-三氟甲基-4-(2-三氟甲基-嘧啶-5-基)-噻唑-5-基]-六氫吡

-1-基}-乙酮；或該等化合物之鹽(詳言之醫藥學上可接受之鹽)。 23) Other examples of compounds of formula (I) as defined in Example 1) are selected from the group consisting of: 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-tri Fluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-2-(3-methyl-pyrazol-1-yl)-ethanone; 2-(3-ethyl-pyrazol-1-yl)-1-{(R)-2- (2-Hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone; 2-(3-cyclopropyl-pyrazol-1-yl)-1-{(R)-2-(2-hydroxy-ethyl)-4-[2-tri Fluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone; 1-{(S)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazole -5-yl]-hexahydropyridine

-1-yl}-2-(3-methyl-pyrazol-1-yl)-ethanone; 2-(3-ethyl-pyrazol-1-yl)-1-{(S)-2- Hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone; and 2-(3-cyclopropyl-pyrazol-1-yl)-1-{(S)-2-hydroxymethyl-4-[2-trifluoromethyl- 4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone; or salts of these compounds (detailed pharmaceutically acceptable salts).

24) The present invention therefore relates to compounds of formula (I) as defined in Example 1), compounds of formula (I _TA ) as defined in Example 8), formula (I) as defined in Example 20) _St1 ) compound, the compound of formula (I _St2 ) as defined in Example 21) and further limited by the characteristics of any one of Examples 2) to 7), 9) to 19), 22) and 23) For these compounds, all compounds consider their respective dependencies; regarding their pharmaceutically acceptable salts; and regarding their use as agents, especially in the treatment of CXCR3 receptor dysfunction or ligand function via CXCR3 signaling Use in disorders related to disorders, such as autoimmune disorders, inflammatory diseases, infectious diseases, transplant rejection, fibrosis, neurodegenerative disorders, and cancer, among others. In particular, the following examples related to the compounds of formulae (I), ( _ITA ), (I _St1 ) and (I _St2 ) are therefore possible and expected, and are specifically disclosed in individualized form: 1, 2+1 , 3+1, 4+1, 4+2+1, 4+3+1, 5+1, 5+2+1, 5+3+1, 6+1, 6+2+1, 6+3 +1, 6+4+1, 6+4+2+1, 6+4+3+1, 6+5+1, 6+5+2+1, 6+5+3+1, 7+1 , 7+2+1, 7+3+1, 7+4+1, 7+4+2+1, 7+4+3+1, 7+5+1, 7+5+2+1, 7 +5+3+1, 7+6+1, 7+6+2+1, 7+6+3+1, 7+6+4+1, 7+6+4+2+1, 7+6 +4+3+1, 7+6+5+1, 7+6+5+2+1, 7+6+5+3+1, 8+1, 9+8+1, 10+8+1 , 11+8+1, 11+9+8+1, 11+10+8+1, 12+8+1, 12+9+8+1, 12+10+8+1, 13+8+1 , 13+9+8+1, 13+11+8+1, 13+11+9+8+1, 13+11+10+8+1, 13+12+8+1, 13+12+9 +8+1, 13+12+10+8+1, 14+8+1, 14+9+8+1, 14+11+8+1, 14+11+9+8+1, 14+11 +10+8+1, 14+12+8+1, 14+12+9+8+1, 14+12+10+8+1, 15+8+1, 15+9+8+1, 15 +10+8+1, 15+11+8+1, 15+11+9+8+1, 15+11+10+8+1, 15+12+8+1, 15+12+9+8 +1, 15+12+10+8+1, 16+8+1, 16+9+8+1, 16+10+8+1, 16+11+8+1, 16+11+9+8 +1, 16+11+10+8+1, 16+12+8+1, 16+12+9+8+1, 16+12+10+8+1, 16+13+8+1, 16 +13+9+8+1, 16+13+11+8+1, 16+13+11+9+8+1, 16+13+11+10+8+1, 16+13+12+8 +1, 16+13+12+9+8+1, 16+13+12+10+8+1, 16+14+8+1, 16+14+9+8+1, 16+14+11 +8+1, 16+14+11+9+8+1, 16+14+11+10+8+1, 16+14+12+8+1, 16+14+12+9+8+1 , 16+14+12+10+8+1, 16+15+8+1, 16+15+9+8+1, 16+15+10+8+1, 1 6+15+11+8+1, 16+15+11+9+8+1, 16+15+11+10+8+1, 16+15+12+8+1, 16+15+12+ 9+8+1, 16+15+12+10+8+1, 17+8+1, 17+9+8+1, 17+10+8+1, 17+11+8+1, 17+ 11+9+8+1, 17+11+10+8+1, 17+12+8+1, 17+12+9+8+1, 17+12+10+8+1, 17+13+ 8+1, 17+13+9+8+1, 17+13+11+8+1, 17+13+11+9+8+1, 17+13+11+10+8+1, 17+ 13+12+8+1, 17+13+12+9+8+1, 17+13+12+10+8+1, 17+14+8+1, 17+14+9+8+1, 17+14+11+8+1, 17+14+11+9+8+1, 17+14+11+10+8+1, 17+14+12+8+1, 17+14+12+ 9+8+1, 17+14+12+10+8+1, 17+15+8+1, 17+15+9+8+1, 17+15+10+8+1, 17+15+ 11+8+1, 17+15+11+9+8+1, 17+15+11+10+8+1, 17+15+12+8+1, 17+15+12+9+8+ 1. 17+15+12+10+8+1, 18+8+1, 18+9+8+1, 18+11+8+1, 18+11+9+8+1, 18+11+ 10+8+1, 18+12+8+1, 18+12+9+8+1, 18+12+10+8+1, 18+13+8+1, 18+13+9+8+ 1. 18+13+11+8+1, 18+13+11+9+8+1, 18+13+11+10+8+1, 18+13+12+8+1, 18+13+ 12+9+8+1, 18+13+12+10+8+1, 18+14+8+1, 18+14+9+8+1, 18+14+11+8+1, 18+ 14+11+9+8+1, 18+14+11+10+8+1, 18+14+12+8+1, 18+14+12+9+8+1, 18+14+12+ 10+8+1, 18+15+8+1, 18+15+9+8+1, 18+15+10+8+1, 18+15+11+8+1, 18+15+11+ 9+8+1, 18+15+11+10+8+1, 18+15+12+8+1, 18+15+12+9+8+1, 18+15+12+10+8+ 1. 18+16+8+1, 18+16+9+8+1, 18+16+10+8+1, 18+16+11+ 8+1, 18+16+11+9+8+1, 18+16+11+10+8+1, 18+16+12+8+1, 18+16+12+9+8+1, 18+16+12+10+8+1, 18+16+13+8+1, 18+16+13+9+8+1, 18+16+13+11+8+1, 18+16+ 13+11+9+8+1, 18+16+13+11+10+8+1, 18+16+13+12+8+1, 18+16+13+12+9+8+1, 18+16+13+12+10+8+1, 18+16+14+8+1, 18+16+14+9+8+1, 18+16+14+11+8+1, 18+ 16+14+11+9+8+1, 18+16+14+11+10+8+1, 18+16+14+12+8+1, 18+16+14+12+9+8+ 1. 18+16+14+12+10+8+1, 18+16+15+8+1, 18+16+15+9+8+1, 18+16+15+10+8+1, 18+16+15+11+8+1, 18+16+15+11+9+8+1, 18+16+15+11+10+8+1, 18+16+15+12+8+ 1. 18+16+15+12+9+8+1, 18+16+15+12+10+8+1, 18+17+8+1, 18+17+9+8+1, 18+ 17+10+8+1, 18+17+11+8+1, 18+17+11+9+8+1, 18+17+11+10+8+1, 18+17+12+8+ 1. 18+17+12+9+8+1, 18+17+12+10+8+1, 18+17+13+8+1, 18+17+13+9+8+1, 18+ 17+13+11+8+1, 18+17+13+11+9+8+1, 18+17+13+11+10+8+1, 18+17+13+12+8+1, 18+17+13+12+9+8+1, 18+17+13+12+10+8+1, 18+17+14+8+1, 18+17+14+9+8+1, 18+17+14+11+8+1, 18+17+14+11+9+8+1, 18+17+14+11+10+8+1, 18+17+14+12+8+ 1. 18+17+14+12+9+8+1, 18+17+14+12+10+8+1, 18+17+15+8+1, 18+17+15+9+8+ 1. 18+17+15+10+8+1, 18+17+15+11+8+1, 18+17+15+11+9+8+1, 18+17+15+11+10+ 8+1, 18+17+15+12+8+ 1. 18+17+15+12+9+8+1, 18+17+15+12+10+8+1, 19+8+1, 19+9+8+1, 19+10+8+ 1. 19+11+8+1, 19+11+9+8+1, 19+11+10+8+1, 19+12+8+1, 19+12+9+8+1, 19+ 12+10+8+1, 19+13+8+1, 19+13+9+8+1, 19+13+11+8+1, 19+13+11+9+8+1, 19+ 13+11+10+8+1, 19+13+12+8+1, 19+13+12+9+8+1, 19+13+12+10+8+1, 19+14+8+ 1. 19+14+9+8+1, 19+14+11+8+1, 19+14+11+9+8+1, 19+14+11+10+8+1, 19+14+ 12+8+1, 19+14+12+9+8+1, 19+14+12+10+8+1, 19+15+8+1, 19+15+9+8+1, 19+ 15+10+8+1, 19+15+11+8+1, 19+15+11+9+8+1, 19+15+11+10+8+1, 19+15+12+8+ 1. 19+15+12+9+8+1, 19+15+12+10+8+1, 19+16+8+1, 19+16+9+8+1, 19+16+10+ 8+1, 19+16+11+8+1, 19+16+11+9+8+1, 19+16+11+10+8+1, 19+16+12+8+1, 19+ 16+12+9+8+1, 19+16+12+10+8+1, 19+16+13+8+1, 19+16+13+9+8+1, 19+16+13+ 11+8+1, 19+16+13+11+9+8+1, 19+16+13+11+10+8+1, 19+16+13+12+8+1, 19+16+ 13+12+9+8+1, 19+16+13+12+10+8+1, 19+16+14+8+1, 19+16+14+9+8+1, 19+16+ 14+11+8+1, 19+16+14+11+9+8+1, 19+16+14+11+10+8+1, 19+16+14+12+8+1, 19+ 16+14+12+9+8+1, 19+16+14+12+10+8+1, 19+16+15+8+1, 19+16+15+9+8+1, 19+ 16+15+10+8+1, 19+16+15+11+8+1, 19+16+15+11+9+8+1, 19+16+15+11+10+8+1, 19+16+15+12+8+1, 19+16+15+12+9+8+1 , 19+16+15+12+10+8+1, 19+17+8+1, 19+17+9+8+1, 19+17+10+8+1, 19+17+11+8 +1, 19+17+11+9+8+1, 19+17+11+10+8+1, 19+17+12+8+1, 19+17+12+9+8+1, 19 +17+12+10+8+1, 19+17+13+8+1, 19+17+13+9+8+1, 19+17+13+11+8+1, 19+17+13 +11+9+8+1, 19+17+13+11+10+8+1, 19+17+13+12+8+1, 19+17+13+12+9+8+1, 19 +17+13+12+10+8+1, 19+17+14+8+1, 19+17+14+9+8+1, 19+17+14+11+8+1, 19+17 +14+11+9+8+1, 19+17+14+11+10+8+1, 19+17+14+12+8+1, 19+17+14+12+9+8+1 , 19+17+14+12+10+8+1, 19+17+15+8+1, 19+17+15+9+8+1, 19+17+15+10+8+1, 19 +17+15+11+8+1, 19+17+15+11+9+8+1, 19+17+15+11+10+8+1, 19+17+15+12+8+1 , 19+17+15+12+9+8+1, 19+17+15+12+10+8+1, 20+1, 20+2+1, 20+3+1, 20+4+1 , 20+4+2+1, 20+4+3+1, 20+5+1, 20+5+2+1, 20+5+3+1, 20+6+1, 20+6+2 +1, 20+6+3+1, 20+6+4+1, 20+6+4+2+1, 20+6+4+3+1, 20+6+5+1, 20+6 +5+2+1, 20+6+5+3+1, 20+7+1, 20+7+2+1, 20+7+3+1, 20+7+4+1, 20+7 +4+2+1, 20+7+4+3+1, 20+7+5+1, 20+7+5+2+1, 20+7+5+3+1, 20+7+6 +1, 20+7+6+2+1, 20+7+6+3+1, 20+7+6+4+1, 20+7+6+4+2+1, 20+7+6 +4+3+1, 20+7+6+5+1, 20+7+6+5+2+1, 20+7+6+5+3+1, 20+8+1, 20+9 +8+1, 20+10+8+1, 20+11+8+1, 20+11+9+8+1, 20+11+10+8+1, 20+12+8+1, 20 +12+9+8+1, 20+12+10 +8+1, 20+13+8+1, 20+13+9+8+1, 20+13+11+8+1, 20+13+11+9+8+1, 20+13+11 +10+8+1, 20+13+12+8+1, 20+13+12+9+8+1, 20+13+12+10+8+1, 20+14+8+1, 20 +14+9+8+1, 20+14+11+8+1, 20+14+11+9+8+1, 20+14+11+10+8+1, 20+14+12+8 +1, 20+14+12+9+8+1, 20+14+12+10+8+1, 20+15+8+1, 20+15+9+8+1, 20+15+10 +8+1, 20+15+11+8+1, 20+15+11+9+8+1, 20+15+11+10+8+1, 20+15+12+8+1, 20 +15+12+9+8+1, 20+15+12+10+8+1, 20+16+8+1, 20+16+9+8+1, 20+16+10+8+1 , 20+16+11+8+1, 20+16+11+9+8+1, 20+16+11+10+8+1, 20+16+12+8+1, 20+16+12 +9+8+1, 20+16+12+10+8+1, 20+16+13+8+1, 20+16+13+9+8+1, 20+16+13+11+8 +1, 20+16+13+11+9+8+1, 20+16+13+11+10+8+1, 20+16+13+12+8+1, 20+16+13+12 +9+8+1, 20+16+13+12+10+8+1, 20+16+14+8+1, 20+16+14+9+8+1, 20+16+14+11 +8+1, 20+16+14+11+9+8+1, 20+16+14+11+10+8+1, 20+16+14+12+8+1, 20+16+14 +12+9+8+1, 20+16+14+12+10+8+1, 20+16+15+8+1, 20+16+15+9+8+1, 20+16+15 +10+8+1, 20+16+15+11+8+1, 20+16+15+11+9+8+1, 20+16+15+11+10+8+1, 20+16 +15+12+8+1, 20+16+15+12+9+8+1, 20+16+15+12+10+8+1, 20+17+8+1, 20+17+9 +8+1, 20+17+10+8+1, 20+17+11+8+1, 20+17+11+9+8+1, 20+17+11+10+8+1, 20 +17+12+8+1, 20+17+12+9+8+1, 20+ 17+12+10+8+1, 20+17+13+8+1, 20+17+13+9+8+1, 20+17+13+11+8+1, 20+17+13+ 11+9+8+1, 20+17+13+11+10+8+1, 20+17+13+12+8+1, 20+17+13+12+9+8+1, 20+ 17+13+12+10+8+1, 20+17+14+8+1, 20+17+14+9+8+1, 20+17+14+11+8+1, 20+17+ 14+11+9+8+1, 20+17+14+11+10+8+1, 20+17+14+12+8+1, 20+17+14+12+9+8+1, 20+17+14+12+10+8+1, 20+17+15+8+1, 20+17+15+9+8+1, 20+17+15+10+8+1, 20+ 17+15+11+8+1, 20+17+15+11+9+8+1, 20+17+15+11+10+8+1, 20+17+15+12+8+1, 20+17+15+12+9+8+1, 20+17+15+12+10+8+1, 20+18+8+1, 20+18+9+8+1, 20+18+ 11+8+1, 20+18+11+9+8+1, 20+18+11+10+8+1, 20+18+12+8+1, 20+18+12+9+8+ 1. 20+18+12+10+8+1, 20+18+13+8+1, 20+18+13+9+8+1, 20+18+13+11+8+1, 20+ 18+13+11+9+8+1, 20+18+13+11+10+8+1, 20+18+13+12+8+1, 20+18+13+12+9+8+ 1. 20+18+13+12+10+8+1, 20+18+14+8+1, 20+18+14+9+8+1, 20+18+14+11+8+1, 20+18+14+11+9+8+1, 20+18+14+11+10+8+1, 20+18+14+12+8+1, 20+18+14+12+9+ 8+1, 20+18+14+12+10+8+1, 20+18+15+8+1, 20+18+15+9+8+1, 20+18+15+10+8+ 1. 20+18+15+11+8+1, 20+18+15+11+9+8+1, 20+18+15+11+10+8+1, 20+18+15+12+ 8+1, 20+18+15+12+9+8+1, 20+18+15+12+10+8+1, 20+18+16+8+1, 20+18+16+9+ 8+1, 20+18+16+10+ 8+1, 20+18+16+11+8+1, 20+18+16+11+9+8+1, 20+18+16+11+10+8+1, 20+18+16+ 12+8+1, 20+18+16+12+9+8+1, 20+18+16+12+10+8+1, 20+18+16+13+8+1, 20+18+ 16+13+9+8+1, 20+18+16+13+11+8+1, 20+18+16+13+11+9+8+1, 20+18+16+13+11+ 10+8+1, 20+18+16+13+12+8+1, 20+18+16+13+12+9+8+1, 20+18+16+13+12+10+8+ 1. 20+18+16+14+8+1, 20+18+16+14+9+8+1, 20+18+16+14+11+8+1, 20+18+16+14+ 11+9+8+1, 20+18+16+14+11+10+8+1, 20+18+16+14+12+8+1, 20+18+16+14+12+9+ 8+1, 20+18+16+14+12+10+8+1, 20+18+16+15+8+1, 20+18+16+15+9+8+1, 20+18+ 16+15+10+8+1, 20+18+16+15+11+8+1, 20+18+16+15+11+9+8+1, 20+18+16+15+11+ 10+8+1, 20+18+16+15+12+8+1, 20+18+16+15+12+9+8+1, 20+18+16+15+12+10+8+ 1. 20+18+17+8+1, 20+18+17+9+8+1, 20+18+17+10+8+1, 20+18+17+11+8+1, 20+ 18+17+11+9+8+1, 20+18+17+11+10+8+1, 20+18+17+12+8+1, 20+18+17+12+9+8+ 1. 20+18+17+12+10+8+1, 20+18+17+13+8+1, 20+18+17+13+9+8+1, 20+18+17+13+ 11+8+1, 20+18+17+13+11+9+8+1, 20+18+17+13+11+10+8+1, 20+18+17+13+12+8+ 1. 20+18+17+13+12+9+8+1, 20+18+17+13+12+10+8+1, 20+18+17+14+8+1, 20+18+ 17+14+9+8+1, 20+18+17+14+11+8+1, 20+18+17+14+11+9+8+1, 20+18+17+14+11 +10+8+1, 20+18+17+14+12+8+1, 20+18+17+14+12+9+8+1, 20+18+17+14+12+10+8 +1, 20+18+17+15+8+1, 20+18+17+15+9+8+1, 20+18+17+15+10+8+1, 20+18+17+15 +11+8+1, 20+18+17+15+11+9+8+1, 20+18+17+15+11+10+8+1, 20+18+17+15+12+8 +1, 20+18+17+15+12+9+8+1, 20+18+17+15+12+10+8+1, 20+19+8+1, 20+19+9+8 +1, 20+19+10+8+1, 20+19+11+8+1, 20+19+11+9+8+1, 20+19+11+10+8+1, 20+19 +12+8+1, 20+19+12+9+8+1, 20+19+12+10+8+1, 20+19+13+8+1, 20+19+13+9+8 +1, 20+19+13+11+8+1, 20+19+13+11+9+8+1, 20+19+13+11+10+8+1, 20+19+13+12 +8+1, 20+19+13+12+9+8+1, 20+19+13+12+10+8+1, 20+19+14+8+1, 20+19+14+9 +8+1, 20+19+14+11+8+1, 20+19+14+11+9+8+1, 20+19+14+11+10+8+1, 20+19+14 +12+8+1, 20+19+14+12+9+8+1, 20+19+14+12+10+8+1, 20+19+15+8+1, 20+19+15 +9+8+1, 20+19+15+10+8+1, 20+19+15+11+8+1, 20+19+15+11+9+8+1, 20+19+15 +11+10+8+1, 20+19+15+12+8+1, 20+19+15+12+9+8+1, 20+19+15+12+10+8+1, 20 +19+16+8+1, 20+19+16+9+8+1, 20+19+16+10+8+1, 20+19+16+11+8+1, 20+19+16 +11+9+8+1, 20+19+16+11+10+8+1, 20+19+16+12+8+1, 20+19+16+12+9+8+1, 20 +19+16+12+10+8+1, 20+19+16+13+8+1, 20+19+16+13+9+8+1, 20+19+16+13+11+8 +1, 20+19+16 +13+11+9+8+1, 20+19+16+13+11+10+8+1, 20+19+16+13+12+8+1, 20+19+16+13+12 +9+8+1, 20+19+16+13+12+10+8+1, 20+19+16+14+8+1, 20+19+16+14+9+8+1, 20 +19+16+14+11+8+1, 20+19+16+14+11+9+8+1, 20+19+16+14+11+10+8+1, 20+19+16 +14+12+8+1, 20+19+16+14+12+9+8+1, 20+19+16+14+12+10+8+1, 20+19+16+15+8 +1, 20+19+16+15+9+8+1, 20+19+16+15+10+8+1, 20+19+16+15+11+8+1, 20+19+16 +15+11+9+8+1, 20+19+16+15+11+10+8+1, 20+19+16+15+12+8+1, 20+19+16+15+12 +9+8+1, 20+19+16+15+12+10+8+1, 20+19+17+8+1, 20+19+17+9+8+1, 20+19+17 +10+8+1, 20+19+17+11+8+1, 20+19+17+11+9+8+1, 20+19+17+11+10+8+1, 20+19 +17+12+8+1, 20+19+17+12+9+8+1, 20+19+17+12+10+8+1, 20+19+17+13+8+1, 20 +19+17+13+9+8+1, 20+19+17+13+11+8+1, 20+19+17+13+11+9+8+1, 20+19+17+13 +11+10+8+1, 20+19+17+13+12+8+1, 20+19+17+13+12+9+8+1, 20+19+17+13+12+10 +8+1, 20+19+17+14+8+1, 20+19+17+14+9+8+1, 20+19+17+14+11+8+1, 20+19+17 +14+11+9+8+1, 20+19+17+14+11+10+8+1, 20+19+17+14+12+8+1, 20+19+17+14+12 +9+8+1, 20+19+17+14+12+10+8+1, 20+19+17+15+8+1, 20+19+17+15+9+8+1, 20 +19+17+15+10+8+1, 20+19+17+15+11+8+1, 20+19+17+15+11+9+8+1, 20+19+17 +15+11+10+8+1, 20+19+17+15+12+8+1, 20+19+17+15+12+9+8+1, 20+19+17+15+12 +10+8+1, 21+1, 21+2+1, 21+3+1, 21+4+1, 21+4+2+1, 21+4+3+1, 21+5+1 , 21+5+2+1, 21+5+3+1, 21+6+1, 21+6+2+1, 21+6+3+1, 21+6+4+1, 21+6 +4+2+1, 21+6+4+3+1, 21+6+5+1, 21+6+5+2+1, 21+6+5+3+1, 21+7+1 , 21+7+2+1, 21+7+3+1, 21+7+4+1, 21+7+4+2+1, 21+7+4+3+1, 21+7+5 +1, 21+7+5+2+1, 21+7+5+3+1, 21+7+6+1, 21+7+6+2+1, 21+7+6+3+1 , 21+7+6+4+1, 21+7+6+4+2+1, 21+7+6+4+3+1, 21+7+6+5+1, 21+7+6 +5+2+1, 21+7+6+5+3+1, 21+8+1, 21+9+8+1, 21+10+8+1, 21+11+8+1, 21 +11+9+8+1, 21+11+10+8+1, 21+12+8+1, 21+12+9+8+1, 21+12+10+8+1, 21+13 +8+1, 21+13+9+8+1, 21+13+11+8+1, 21+13+11+9+8+1, 21+13+11+10+8+1, 21 +13+12+8+1, 21+13+12+9+8+1, 21+13+12+10+8+1, 21+14+8+1, 21+14+9+8+1 , 21+14+11+8+1, 21+14+11+9+8+1, 21+14+11+10+8+1, 21+14+12+8+1, 21+14+12 +9+8+1, 21+14+12+10+8+1, 21+15+8+1, 21+15+9+8+1, 21+15+10+8+1, 21+15 +11+8+1, 21+15+11+9+8+1, 21+15+11+10+8+1, 21+15+12+8+1, 21+15+12+9+8 +1, 21+15+12+10+8+1, 21+16+8+1, 21+16+9+8+1, 21+16+10+8+1, 21+16+11+8 +1, 21+16+11+9+8+1, 21+16+11+10+8+1, 21+16+12+8+1, 21+16+12+9+8+1, 21 +16+12+10+8+1, 21+16+13+8+1, 2 1+16+13+9+8+1, 21+16+13+11+8+1, 21+16+13+11+9+8+1, 21+16+13+11+10+8+ 1. 21+16+13+12+8+1, 21+16+13+12+9+8+1, 21+16+13+12+10+8+1, 21+16+14+8+ 1. 21+16+14+9+8+1, 21+16+14+11+8+1, 21+16+14+11+9+8+1, 21+16+14+11+10+ 8+1, 21+16+14+12+8+1, 21+16+14+12+9+8+1, 21+16+14+12+10+8+1, 21+16+15+ 8+1, 21+16+15+9+8+1, 21+16+15+10+8+1, 21+16+15+11+8+1, 21+16+15+11+9+ 8+1, 21+16+15+11+10+8+1, 21+16+15+12+8+1, 21+16+15+12+9+8+1, 21+16+15+ 12+10+8+1, 21+17+8+1, 21+17+9+8+1, 21+17+10+8+1, 21+17+11+8+1, 21+17+ 11+9+8+1, 21+17+11+10+8+1, 21+17+12+8+1, 21+17+12+9+8+1, 21+17+12+10+ 8+1, 21+17+13+8+1, 21+17+13+9+8+1, 21+17+13+11+8+1, 21+17+13+11+9+8+ 1. 21+17+13+11+10+8+1, 21+17+13+12+8+1, 21+17+13+12+9+8+1, 21+17+13+12+ 10+8+1, 21+17+14+8+1, 21+17+14+9+8+1, 21+17+14+11+8+1, 21+17+14+11+9+ 8+1, 21+17+14+11+10+8+1, 21+17+14+12+8+1, 21+17+14+12+9+8+1, 21+17+14+ 12+10+8+1, 21+17+15+8+1, 21+17+15+9+8+1, 21+17+15+10+8+1, 21+17+15+11+ 8+1, 21+17+15+11+9+8+1, 21+17+15+11+10+8+1, 21+17+15+12+8+1, 21+17+15+ 12+9+8+1, 21+17+15+12+10+8+1, 21+18+8+1, 21+18+9+8+1, 21+18+11+8+1, 21+18+11+9+8+1, 21+1 8+11+10+8+1, 21+18+12+8+1, 21+18+12+9+8+1, 21+18+12+10+8+1, 21+18+13+ 8+1, 21+18+13+9+8+1, 21+18+13+11+8+1, 21+18+13+11+9+8+1, 21+18+13+11+ 10+8+1, 21+18+13+12+8+1, 21+18+13+12+9+8+1, 21+18+13+12+10+8+1, 21+18+ 14+8+1, 21+18+14+9+8+1, 21+18+14+11+8+1, 21+18+14+11+9+8+1, 21+18+14+ 11+10+8+1, 21+18+14+12+8+1, 21+18+14+12+9+8+1, 21+18+14+12+10+8+1, 21+ 18+15+8+1, 21+18+15+9+8+1, 21+18+15+10+8+1, 21+18+15+11+8+1, 21+18+15+ 11+9+8+1, 21+18+15+11+10+8+1, 21+18+15+12+8+1, 21+18+15+12+9+8+1, 21+ 18+15+12+10+8+1, 21+18+16+8+1, 21+18+16+9+8+1, 21+18+16+10+8+1, 21+18+ 16+11+8+1, 21+18+16+11+9+8+1, 21+18+16+11+10+8+1, 21+18+16+12+8+1, 21+ 18+16+12+9+8+1, 21+18+16+12+10+8+1, 21+18+16+13+8+1, 21+18+16+13+9+8+ 1. 21+18+16+13+11+8+1, 21+18+16+13+11+9+8+1, 21+18+16+13+11+10+8+1, 21+ 18+16+13+12+8+1, 21+18+16+13+12+9+8+1, 21+18+16+13+12+10+8+1, 21+18+16+ 14+8+1, 21+18+16+14+9+8+1, 21+18+16+14+11+8+1, 21+18+16+14+11+9+8+1, 21+18+16+14+11+10+8+1, 21+18+16+14+12+8+1, 21+18+16+14+12+9+8+1, 21+18+ 16+14+12+10+8+1, 21+18+16+15+8+1, 21+18+16+15+9+8+1, 21+18+16+15+10+8+ 1, 21+18+ 16+15+11+8+1, 21+18+16+15+11+9+8+1, 21+18+16+15+11+10+8+1, 21+18+16+15+ 12+8+1, 21+18+16+15+12+9+8+1, 21+18+16+15+12+10+8+1, 21+18+17+8+1, 21+ 18+17+9+8+1, 21+18+17+10+8+1, 21+18+17+11+8+1, 21+18+17+11+9+8+1, 21+ 18+17+11+10+8+1, 21+18+17+12+8+1, 21+18+17+12+9+8+1, 21+18+17+12+10+8+ 1. 21+18+17+13+8+1, 21+18+17+13+9+8+1, 21+18+17+13+11+8+1, 21+18+17+13+ 11+9+8+1, 21+18+17+13+11+10+8+1, 21+18+17+13+12+8+1, 21+18+17+13+12+9+ 8+1, 21+18+17+13+12+10+8+1, 21+18+17+14+8+1, 21+18+17+14+9+8+1, 21+18+ 17+14+11+8+1, 21+18+17+14+11+9+8+1, 21+18+17+14+11+10+8+1, 21+18+17+14+ 12+8+1, 21+18+17+14+12+9+8+1, 21+18+17+14+12+10+8+1, 21+18+17+15+8+1, 21+18+17+15+9+8+1, 21+18+17+15+10+8+1, 21+18+17+15+11+8+1, 21+18+17+15+ 11+9+8+1, 21+18+17+15+11+10+8+1, 21+18+17+15+12+8+1, 21+18+17+15+12+9+ 8+1, 21+18+17+15+12+10+8+1, 21+19+8+1, 21+19+9+8+1, 21+19+10+8+1, 21+ 19+11+8+1, 21+19+11+9+8+1, 21+19+11+10+8+1, 21+19+12+8+1, 21+19+12+9+ 8+1, 21+19+12+10+8+1, 21+19+13+8+1, 21+19+13+9+8+1, 21+19+13+11+8+1, 21+19+13+11+9+8+1, 21+19+13+11+10+8+1, 21+19+13+12+8+1, 21+19+13+12+9+ 8+1, 21+19+13+12+10+8+1, 21+19+14+8+1, 21+19+14+9+8+1, 21+19+14+11+8+1, 21+ 19+14+11+9+8+1, 21+19+14+11+10+8+1, 21+19+14+12+8+1, 21+19+14+12+9+8+ 1. 21+19+14+12+10+8+1, 21+19+15+8+1, 21+19+15+9+8+1, 21+19+15+10+8+1, 21+19+15+11+8+1, 21+19+15+11+9+8+1, 21+19+15+11+10+8+1, 21+19+15+12+8+ 1. 21+19+15+12+9+8+1, 21+19+15+12+10+8+1, 21+19+16+8+1, 21+19+16+9+8+ 1. 21+19+16+10+8+1, 21+19+16+11+8+1, 21+19+16+11+9+8+1, 21+19+16+11+10+ 8+1, 21+19+16+12+8+1, 21+19+16+12+9+8+1, 21+19+16+12+10+8+1, 21+19+16+ 13+8+1, 21+19+16+13+9+8+1, 21+19+16+13+11+8+1, 21+19+16+13+11+9+8+1, 21+19+16+13+11+10+8+1, 21+19+16+13+12+8+1, 21+19+16+13+12+9+8+1, 21+19+ 16+13+12+10+8+1, 21+19+16+14+8+1, 21+19+16+14+9+8+1, 21+19+16+14+11+8+ 1. 21+19+16+14+11+9+8+1, 21+19+16+14+11+10+8+1, 21+19+16+14+12+8+1, 21+ 19+16+14+12+9+8+1, 21+19+16+14+12+10+8+1, 21+19+16+15+8+1, 21+19+16+15+ 9+8+1, 21+19+16+15+10+8+1, 21+19+16+15+11+8+1, 21+19+16+15+11+9+8+1, 21+19+16+15+11+10+8+1, 21+19+16+15+12+8+1, 21+19+16+15+12+9+8+1, 21+19+ 16+15+12+10+8+1, 21+19+17+8+1, 21+19+17+9+8+1, 21+19+17+10+8+1, 21+19+ 17+ 11+8+1, 21+19+17+11+9+8+1, 21+19+17+11+10+8+1, 21+19+17+12+8+1, 21+19+ 17+12+9+8+1, 21+19+17+12+10+8+1, 21+19+17+13+8+1, 21+19+17+13+9+8+1, 21+19+17+13+11+8+1, 21+19+17+13+11+9+8+1, 21+19+17+13+11+10+8+1, 21+19+ 17+13+12+8+1, 21+19+17+13+12+9+8+1, 21+19+17+13+12+10+8+1, 21+19+17+14+ 8+1, 21+19+17+14+9+8+1, 21+19+17+14+11+8+1, 21+19+17+14+11+9+8+1, 21+ 19+17+14+11+10+8+1, 21+19+17+14+12+8+1, 21+19+17+14+12+9+8+1, 21+19+17+ 14+12+10+8+1, 21+19+17+15+8+1, 21+19+17+15+9+8+1, 21+19+17+15+10+8+1, 21+19+17+15+11+8+1, 21+19+17+15+11+9+8+1, 21+19+17+15+11+10+8+1, 21+19+ 17+15+12+8+1, 21+19+17+15+12+9+8+1, 21+19+17+15+12+10+8+1, 22+1 and 23+1; In the above list, the numbers refer to the embodiments according to the embodiment numbers provided above, and the "+" indicates the dependency with another embodiment. Different individualized embodiments are separated by a comma. In other words, for example, "4+2+1" refers to embodiment 4) attached to embodiment 2), attached to embodiment 1), that is, embodiment "4+2+1" corresponds to the further embodiment The compounds of Example 1) are restricted by the characteristics of 2) and 4).

When a plural form is used for a compound, salt, pharmaceutical composition, disease or analogue thereof, this is also intended to mean a single compound, salt, pharmaceutical composition, disease or analogue thereof.

Where appropriate and advantageous, any reference to compounds of formula (I) as defined in any one of Examples 1) to 24) should be understood to also refer to salts of such compounds (and especially pharmaceutically acceptable salt).

The term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the compounds of the present invention and exhibit minimal undesired toxicological effects. Depending on the presence of basic and/or acidic groups in the compounds of the invention, these salts include inorganic or organic acid and/or base addition salts. For references, see for example "Handbook of Pharmaceutical Salts. Properties, Selection and Use.", P. Heinrich Stahl, Camille G. Wermuth (ed.), Wiley-VCH, 2008, and "Pharmaceutical Salts and Co-crystals", Johan Wouters And Luc Quéré (eds.), RSC Publishing, 2012.

The present invention also includes isotopically labeled, especially ² H (deuterium)-labeled compounds of formula (I), except that one or more atoms have each had the same atomic number, but the atomic mass is different from the atomic mass generally seen in nature Other than atomic substitution, it is the same as the compound of formula (I). Compounds of the formula (I) and salts thereof labeled with isotopes, especially ² H (deuterium), are within the scope of the present invention. Substituting the heavier isotope ² H (deuterium) for hydrogen can produce greater metabolic stability, such as prolonging the half-life in vivo or lowering the dosage requirements, or can result in reduced inhibition of cytochrome P450 enzymes, for example, improving safety profiles. In one embodiment of the invention, the compound of formula (I) is not isotopically labeled or it is labeled only with one or more deuterium atoms. In a sub-embodiment, the compound of formula (I) is completely unisotopically labeled. Isotopically labeled compounds of formula (I) can be prepared similarly to the methods described below, but using appropriate isotopic variants suitable for reagents or starting materials.

Whenever the term "between" is used to describe a numerical range, it should be understood that the endpoints of the indicated range are explicitly included in the range. For example: if the temperature range is described as between 40°C and 80°C, then this means that the end points of 40°C and 80°C are included in the range; or if the variable is defined as 1 An integer between and 4 means that the variable is an integer 1, 2, 3, or 4.

Unless used with regard to temperature, the term "about" (or "approximately") placed before the value "X" in this application refers to an interval extending from X minus 10% X to X plus 10% X, and Preferably, it refers to an interval extending from X minus 5% X to X plus 5% X. In the special case of temperature, the term "about" (or "approximately") placed before the temperature "Y" in this application refers to an interval extending from the temperature Y minus 10°C to Y plus 10°C, and Preferably, it refers to a range extending from Y minus 5°C to Y plus 5°C. In addition, the term "room temperature" as used herein refers to a temperature of about 25°C.

The compound of formula (I) and its pharmaceutically acceptable salt as defined in any one of Examples 1) to 24) can be used as a medicament, for example, in the form of a pharmaceutical composition for enteral use (this is especially oral) Or parenteral (including topical application or inhalation) administration.

In any way familiar to those skilled in the art (see for example Remington, The Science and Practice of Pharmacy , 21st Edition (2005), Part 5, "Pharmaceutical Manufacturing" [published by Lippincott Williams & Wilkins]), by Combine the described compound of formula (I) or a pharmaceutically acceptable salt thereof (as appropriate with other therapeutically valuable substances) with a suitable non-toxic inert therapeutically compatible solid or liquid carrier material and (if necessary) commonly used The pharmaceutical adjuvant is made into a galenical administration form together to achieve the preparation of the pharmaceutical composition.

The present invention also relates to a method for preventing or treating the diseases or conditions mentioned herein, which comprises administering to a subject a pharmaceutically active amount of a compound of formula (I) as defined in any one of Examples 1) to 24).

In a preferred embodiment of the present invention, it comprises between 1 mg and 1000 mg per day, specifically between 5 mg and 500 mg per day, more specifically between 25 mg and 400 mg per day, especially between 50 mg and 200 mg per day. With volume.

To avoid any doubts, if the compounds are described as suitable for the prevention or treatment of certain diseases, the compounds are also suitable for the preparation of medicaments for the prevention or treatment of such diseases.

Another aspect of the present invention relates to a method for preventing or treating a disease or disorder as mentioned below in a patient, which comprises administering to the patient a pharmaceutically active amount as in any one of Examples 1) to 24) The compound of formula (I) as defined in the item or a pharmaceutically acceptable salt thereof.

The compound according to formula (I) or a pharmaceutically acceptable salt thereof as defined in any one of embodiments 1) to 24) is suitable for preventing or treating coordination with CXCR3 receptor dysfunction or via CXCR3 signaling Conditions related to physical dysfunction.

These disorders related to dysfunction of the CXCR3 receptor or its ligands are diseases or disorders that require modulators of human CXCR3 receptors. The disorders mentioned above can be defined in detail as including autoimmune disorders, inflammatory diseases, infectious diseases, transplant rejection, fibrosis, neurodegenerative disorders, and cancer.

Autoimmune disorders can be defined as including rheumatoid arthritis (RA); multiple sclerosis (MS); inflammatory bowel disease (IBD; including Crohn's disease and ulcerative colitis); systemic lupus erythematosus Syndrome (SLE); psoriasis; psoriatic arthritis; lupus nephritis; interstitial cystitis; celiac disease; antiphospholipid syndrome; thyroiditis such as Hashimoto's thyroiditis; lymphocytic thyroiditis; myasthenia gravis Weakness; Type I diabetes; Uveitis; upper scleritis; scleritis; Kawasaki's disease; uveitis-retinitis; posterior uveitis; uveitis associated with Behcet's disease ; Ocular pigment meningitis syndrome; allergic encephalomyelitis; atopic diseases, such as rhinitis, conjunctivitis, dermatitis; and post-infectious autoimmune diseases, including rheumatic fever and post-infectious silkball nephritis.

Inflammatory diseases can be defined as including asthma; COPD; atherosclerosis; myocarditis; dry eye syndrome (including Sjögren's dry eye syndrome); myopathy (including inflammatory myopathy); sarcomatosis; Pulmonary arterial hypertension, which is particularly associated with sarcomatosis; and obesity.

Infectious diseases can be defined as including diseases mediated by various infectious agents and complications resulting therefrom; such as malaria, cerebral malaria, leprosy, tuberculosis, influenza, Toxoplasma gondii (toxoplasma gondii), dengue, dengue, hepatitis B and C, herpes simplex, leishmania, chlamydia trachomatis, lyme disease, West Nile virus ( west nile virus).

Transplant rejection can be defined as rejection involving transplanted organs (such as kidney, liver, heart, lung, pancreas, cornea, and skin); graft versus host disease; and chronic allograft vascular disease.

Fibrosis can be defined as including cirrhosis (including primary biliary cirrhosis (PBC) and autoimmune hepatitis), idiopathic pulmonary fibrosis, renal fibrosis, endocardial myocardial fibrosis, and systemic sclerosis And joint fibrosis.

Neurodegenerative disorders can be defined as conditions that include neurodegeneration and neuronal death, such as multiple sclerosis (including relapsing-remitting multiple sclerosis and progressive multiple sclerosis), Alzheimer's disease, Parkinson's disease (Parkinson's disease) disease), Huntington's disease, HIV-related dementia, prion-mediated neurodegeneration, epilepsy, stroke, cerebral ischemia, cerebral palsy, optic neuromyelitis, clinical single syndrome, Alpers' disease, Amyotrophic lateral sclerosis (ALS), Alzheimer's disease, dementia with Lewy bodies, Rett syndrome, spinal cord trauma, traumatic brain injury, trigeminal neuralgia, chronic inflammatory demyelination Polyneuropathy, Guillain-Barré syndrome, narcolepsy, glossopharyngeal neuralgia, mild cognitive decline, cognitive decline, spinal muscular atrophy, and cerebral malaria.

Cancer can be defined as encompassing all types of cancer, such as colorectal cancer, rectal cancer, breast cancer, lung cancer, non-small cell lung cancer, prostate cancer, esophageal cancer, gastric cancer, liver cancer, bile duct cancer, spleen cancer, kidney cancer, bladder cancer, uterine cancer , Ovarian cancer, cervical cancer, testicular cancer, thyroid cancer, pancreatic cancer, brain tumors, blood tumors, basophilic adenomas, prolactinoma, hyperprolactinemia, adenoma, endometrial cancer, Colon cancer; chronic lymphocytic leukemia (CLL); and especially the metastatic spread of their cancers.

The compound of formula (I) according to any one of embodiments 1) to 24) or its pharmaceutically acceptable Salt is particularly suitable for preventing or treating one, several or all diseases selected from the group of the following diseases and conditions: 1) selected from rheumatoid arthritis (RA); multiple sclerosis (MS); inflammatory bowel Diseases (IBD; including Crohn's disease and ulcerative colitis); systemic lupus erythematosus (SLE); psoriasis; lupus nephritis; and autoimmune disorders of type 1 diabetes; 2) selected from COPD; dry eyes Syndrome (including Huguelian Dry Eye Syndrome); inflammatory disease of myopathy (including inflammatory myopathy) and sarcomatosis; 3) transplant rejection selected from graft versus host disease; 4) selected from cirrhosis (including Primary biliary cirrhosis (PBC) and autoimmune hepatitis) fibrosis; and 5) a neurodegenerative disorder selected from Guillain-Barré syndrome.

The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of embodiments 1) to 24) is best suited for the treatment of diseases selected from the group consisting of rheumatoid arthritis, multiple sclerosis, Optic neuromyelitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, systemic lupus erythematosus, psoriasis, psoriatic arthritis, lupus nephritis, interstitial cystitis, celiac disease, myasthenia gravis , Type I diabetes, uveitis, asthma, chronic obstructive pulmonary disease, atherosclerosis, myocarditis, inflammatory myopathy, dry eye disease, sarcomatosis, influenza, cerebral malaria, transplant rejection, liver cirrhosis, systemic Sclerosis, pulmonary arterial hypertension, neurodegenerative disease, Alzheimer's disease, HIV-related dementia, Huntington's disease, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, brain tumors, Metastatic spread of colon cancer, breast cancer, or cancer.

Preparation of compound of formula (I)

Another aspect of the present invention is a method for preparing the compound of formula (I). The general order of the reactants (where n, X, R ¹ and R ^{2 are} as defined for formula (I)) may be commercially available or well-known according to the method described in the experimental section by a similar method or according to the outline below Starting compounds to prepare compounds of formula (I) according to the invention. Other abbreviations used in this text are clearly defined or as defined in the experimental section. In some cases, the general groups R ¹ and R ² may not be compatible with the combination described in the scheme below and therefore will require the use of a protecting group (PG). The use of protecting groups is well known in the art (see for example "Protective Groups in Organic Synthesis", TW Greene, PGMWuts, Wiley-Interscience, 1999). For the purposes of this discussion, it will be assumed that these protecting groups are present in place as needed. The compounds obtained can also be converted into salts in a manner known per se, especially their pharmaceutically acceptable salts.

General preparation route:

The compound of formula (I) can be prepared from the intermediate (1) saponified under standard conditions (such as aqueous NaOH in MeOH) as a starting material to obtain the compound of structure (2) (Scheme 1). The carboxylic acid group in the compound of structure (2) is converted to the corresponding bromine (3) using (bis(acetyloxy)iodo)benzene and LiBr in THF at room temperature. Standard conditions for the Suzuki reaction (Suzuki reaction) can be used for coupling partners of structure (4) (where R represents hydrogen or (C _1-4 )alkyl), such as the use of suitable bases (such as aqueous Na ₂ CO ₃ ), Suitable for palladium catalysts (such as Pd(PPh ₃ ) ₂ Cl ₂ ) and suitable solvents (such as MeCN), Suzuki coupling is preferably performed at a temperature of about 80°C. The Boc protecting group of the intermediate (5) obtained can then be preferably cleaved under acidic conditions using HCl in a suitable solvent (such as dioxane) at a temperature of about RT to obtain the compound of structure (6). Standard peptide coupling methods (such as HATU), in the presence of a suitable base (such as DIPEA or NEt ₃ ), and in a suitable solvent (such as DCM or DMF) can be used in the final step with amide coupled with the carboxylic acid derivative (7) ), the compound of formula (I) is preferably obtained at about room temperature.

衍生物(8)在適合鹼(諸如DIPEA)存在下在適合溶劑(諸如MeCN)中且在大約80℃溫度下的親核芳族取代提供結構(1)之化合物。 The compound of structure (1) can be synthesized following the reaction sequence outlined in Scheme 2. Commercially available 2-(trifluoromethyl)thiazole-4-carboxylic acid was treated with n-butyllithium and bromine in THF at a temperature of about -78°C. The resulting brominated compound can be esterified using concentrated sulfuric acid in MeOH and heating at a temperature of about 70°C. Use commercially available hexahydropyridine

The derivative (8) nucleophilic aromatic substitution in the presence of a suitable base (such as DIPEA) in a suitable solvent (such as MeCN) and at a temperature of about 80°C provides the compound of structure (1).

The compound of formula (7) can be obtained from commercially available products or can be synthesized following the route shown in Scheme 3.

Acetic acid derivatives of the formula X-CH ₂ -COO(PG) (where X is a leaving group such as bromine, and PG is a protecting group suitable for acid function (eg benzyl)) can be used, in the base ( The compound of structure (9) is alkylated in the presence of a suitable solvent (such as MeCN or THF) in the presence of Cs ₂ CO ₃ or NaH, and at a temperature of approximately room temperature or 0° C., respectively.

The removal of the protecting group of intermediate (10) (such as the removal of the benzyl protecting group) at approximately room temperature using Pd/C as a catalyst and EtOH as a solvent under H ₂ yields the compound of structure (7). Alternatively, the third butyl group as the protective group PG in the intermediate (10) can be removed by treatment with dioxane-containing HCl at about room temperature. Other suitable acid-functional protecting groups and methods for protecting and removing protecting groups are well known to those skilled in the art (see especially "Protective groups in organic synthesis", Greene TW and Wuts PGM, Wiley-Interscience, 1999).

If a commercially available product is not available, the compound of structure (9) can be prepared by condensing imidate (such as ethyl imidate) and carboxylic acid hydrazine (such as propionate hydrazide) (where R ¹ represents Disubstituted 1 H -1,2,4-triazole derivatives, such as, for example, 3-ethyl-5-methyl-1H-[1,2,4]triazole).

The compound of structure (4) can be obtained from a commercially available product or can be prepared similarly to methods known to those skilled in the art, such as: 5-bromo-pyrimidine or 3-bromo-pyridine derivatives and triisoboric acid respectively Propyl ester and n-BuLi are reacted in THF and toluene at a temperature of about -78°C.

Whenever the compound of formula (I) is obtained as a mixture of enantiomers, the enantiomers can be separated using methods known to those skilled in the art: for example by forming and separating diastereomeric salts or by HPLC on a palm stationary phase (such as Daicel ChiralPak IC (5 μm) column). Typical conditions for palm HPLC are an isotopic solvent mixture of dissolving agent A (EtOH or i PrOH, with or without the presence of amines such as NEt ₃ or DEA) and dissolving agent B (hexane or MeCN) at a flow rate of 0.8 to 16 mL /min.

Experimental part:

Abbreviations (as used in this article and the description above) :

I. Chemistry

The following examples illustrate the preparation of biologically active compounds of the present invention, but do not limit its scope.

Summary: All temperatures are stated in degrees Celsius (°C). Unless otherwise indicated, the reaction took place at room temperature under an argon atmosphere and was carried out in a flame-dried round bottom flask equipped with a magnetic stir bar.

Characterization method used:

The following dissolution conditions have been used to obtain LC-MS residence time:

I) LC-MS (A): Zorbax SB-Aq, 3.5 μm, 4.6×50 mm column, which was thermostatically adjusted at 40°C. The two dissociation solvents are as follows: solvent A = water + 0.04% TFA; solvent B = MeCN. The flow rate of the dissolving agent is 4.5 mL/min, and the characteristics of the dissolving mixture ratio changing with the time t from the start of dissociation are summarized in the following table (a linear gradient is used between two consecutive time points):

II) LC-MS (B): An Acquity UPLC HSS T3 C18 1.8 μm 2.1×50 mm ID column from Waters thermostatically adjusted in an Acquity UPLC column manager (60° C.) was used. The two dissociation solvents are as follows: solvent A = water + 0.05% formic acid; solvent B = MeCN + 0.045% formic acid. The flow rate of the dissolving agent is 1 mL/min, and the characteristics of the dissolution mixture ratio changing with the time t from the start of dissociation are summarized in the following table (a linear gradient is used between two consecutive time points):

III) LC-MS (C): Acquity UPLC CSH C18 1.7 μm 2.1×50mm ID column from Waters thermostatically adjusted in Acquity UPLC Column Manager (60°C). The two dissociation solvents are as follows: solvent A = water + 0.05% formic acid; solvent B = MeCN + 0.045% formic acid. The flow rate of the dissolving agent is 1 mL/min, and the characteristics of the dissolution mixture ratio changing with the time t from the start of dissociation are summarized in the following table (a linear gradient is used between two consecutive time points):

Compound purity and consistency were further confirmed by NMR spectroscopic analysis (Bruker Avance II 400MHz UltrashieldTM or Bruker AscendTM 500 equipped with a 5mm DCH cryogenic probe), 1H (400MHz or 500MHz), and 19F (376MHz). The chemical shift is reported in parts per million (ppm) relative to tetramethylsilane (TMS) or trichlorofluoromethane, and multimodality is given in the form of s (single peak) or m (multiple peak).

Preparative LC-MS method used:

Purification by preparative LC-MS was performed using the conditions described below.

I) Preparative LC-MS (I): X-Bridge column (Waters C18, 10 μm OBD, 30×75 mm) was used. The two dissolution solvents are as follows: Solvent A = water + 0.5% NH ₄ OH (25%); Solvent B = MeCN. The flow rate of the dissolving agent is 75 mL/min, and the characteristics of the dissolution mixture ratio varying with the time t from the start of dissociation are summarized in the following table (a linear gradient is used between two consecutive time points):

II) Preparative LC-MS (II): X-Bridge column (Waters C18, 10 μm OBD, 30×75 mm) was used. The two dissolution solvents are as follows: Solvent A = water + 0.5% NH ₄ OH (25%); Solvent B = MeCN. The flow rate of the dissolving agent is 75 mL/min, and the characteristics of the dissolution mixture ratio varying with the time t from the start of dissociation are summarized in the following table (a linear gradient is used between two consecutive time points):

III) Preparative LC-MS (III): Atlantis column (Waters T3, 10 μm OBD, 30×75 mm) was used. The two dissolution solvents are as follows: Solvent A = water + 0.5% formic acid; Solvent B = MeCN. The flow rate of the dissolving agent is 75 mL/min, and the characteristics of the dissolution mixture ratio varying with the time t from the start of dissociation are summarized in the following table (a linear gradient is used between two consecutive time points):

IV) Preparative LC-MS (IV): Atlantis column (Waters T3, 10 μm OBD, 30×75 mm) was used. The two dissolution solvents are as follows: Solvent A = water + 0.5% formic acid; Solvent B = MeCN. The flow rate of the dissolving agent is 75 mL/min, and the characteristics of the dissolution mixture ratio varying with the time t from the start of dissociation are summarized in the following table (a linear gradient is used between two consecutive time points):

V) Preparative LC-MS (V): X-Bridge column (Waters C18, 10 μm OBD, 30×75 mm) was used. The two dissolution solvents are as follows: Solvent A = water + 0.5% NH ₄ OH (25%); Solvent B = MeCN. The flow rate of the dissolving agent is 75 mL/min, and the characteristics of the dissolution mixture ratio varying with the time t from the start of dissociation are summarized in the following table (a linear gradient is used between two consecutive time points):

VI) Preparative LC-MS (VI): Atlantis column (Waters T3, 10 μm OBD, 30×75 mm) was used. The two dissolution solvents are as follows: Solvent A = water + 0.5% formic acid; Solvent B = MeCN. The flow rate of the dissolving agent is 75 mL/min, and the characteristics of the dissolution mixture ratio varying with the time t from the start of dissociation are summarized in the following table (a linear gradient is used between two consecutive time points):

Preparative para-palm HPLC method used: Purification by preparative para-palm HPLC was performed using the conditions described below.

I) Preparative palmtop HPLC (I): ChiralPak IB column (5 μm, 30×250 mm) was used. The dissolution solvent was Hep/EtOH/DEA 50/50/0.1 for 10 minutes and was run at a flow rate of 16 mL/min.

II) Preparative palmtop HPLC (II): ChiralPak IF column (5 μm, 20×250 mm) was used. The dissolution solvent was Hep/EtOH 50/50 for 8.7 minutes and was run at a flow rate of 19 mL/min.

III) Preparative HPLC (III): (R, R) Whelk-01 column (10 μm, 50×250 mm) was used. The dissolution solvent was Hep/EtOH 70/30 for 16.3 minutes and was run at a flow rate of 100 mL/min.

IV) Preparative palmtop HPLC (IV): ChiralPak IB column (5 μm, 30×250 mm) was used. The dissolution solvent was Hep/EtOH 70/30 for 11.8 minutes and was run at a flow rate of 34 mL/min.

V) Preparative palmtop HPLC (V): ChiralPak IB column (5 μm, 30×250 mm) was used. The dissolution solvent was Hep/EtOH 50/50 for 7.6 minutes and was run at a flow rate of 34 mL/min.

VI) Preparative palmtop HPLC (VI): ChiralPak IB column (5 μm, 30×250 mm) was used. The dissolution solvent was Hep/EtOH 60/40 for 9 minutes and was run at a flow rate of 40 mL/min.

VII) Preparative palmtop HPLC (VII): ChiralPak IC column (5 μm, 30×250 mm) was used. The dissolution solvent was Hep/EtOH 70/30 for 12 minutes and was run at a flow rate of 34 mL/min.

Example 1: 2-(3-tert-butyl-[1,2,4]triazol-1-yl)-1-{(S)-2-hydroxymethyl-4-[2-trifluoromethyl -4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone 1.1. 5-Bromo-2-trifluoromethyl-thiazole-4-carboxylic acid

To a solution of 2-(trifluoromethyl)thiazole-4-carboxylic acid (3.2g) cooled in -78°C in anhydrous THF (60mL) was added dropwise n-BuLi (1.6M) over 15 minutes under argon In hexane, 21.3 mL) so that the internal temperature does not rise above -60 °C. Then a solution of Br ₂ (0.92 mL) in cyclohexane (8 mL) was added dropwise to keep the internal temperature below -60 °C. The resulting mixture was stirred at -78 °C for 2 hours and carefully quenched by adding water (50 mL). Citric acid (10%) was added until pH=2 and the mixture was extracted with EA. The organic layer was washed with brine, dried (MgSO ₄ ), filtered off and evaporated to dryness to obtain 4.15 g of brown solid, which was used without further purification. LC-MS (A): t _R = 0.67 min. F-NMR (CD ₃ OD): -63.57 ppm (s).

1.2. Methyl 5-bromo-2-trifluoromethyl-thiazole-4-carboxylate

To a solution of intermediate 1.1 (12 g), MeOH (130 mL), H ₂ SO ₄ (96%, 6.5 mL) was added, and the mixture was stirred at 70° C. for 3 hours. After cooling, the reaction mixture was quenched with saturated aqueous Na ₂ CO ₃ and the solvent was partially evaporated. The residue was diluted with DCM and washed with saturated aqueous Na ₂ CO ₃ (1×), water (1×) and brine (1×), and the aqueous phase was extracted with DCM (2×). The combined organic layer was dried over MgSO ₄ , filtered off, evaporated and dried under high vacuum to obtain 12 g of brown resin. LC-MS (A): t _R = 0.83 min. F-NMR (CD ₃ OD): -63.59 ppm (s).

1.3. (S)-2-Hydroxymethyl-4-(4-methoxycarbonyl-2-trifluoromethyl-thiazol-5-yl)-hexahydropyridine

Tert-Butyl-1-carboxylate

(3.07g)及DIPEA(3.54mL)。在80℃下攪拌反應混合物28小時。冷卻後，反應混合物用EA稀釋且用水(2×)及鹽水洗滌。用EA萃取水層。經合併之有機層經MgSO₄乾燥，過濾出且蒸發至乾燥。藉由CC(Biotage，SNAP 340g，溶劑A：Hep；溶劑B：EA；以%B計之梯度：歷經3CV 30，歷經5CV 30至50，歷經3CV 50) 純化粗產物，獲得4g黃色泡沫。LC-MS(A)：t_R=0.87min；[M+H]⁺：426.0。 To a solution of intermediate 1.2 (4g) in MeCN (100mL) was added (S)-1-Boc-2-hydroxymethylhexahydropyridine at room temperature

(3.07g) and DIPEA (3.54mL). The reaction mixture was stirred at 80°C for 28 hours. After cooling, the reaction mixture was diluted with EA and washed with water (2×) and brine. The aqueous layer was extracted with EA. The combined organic layer was dried over MgSO ₄ , filtered off and evaporated to dryness. The crude product was purified by CC (Biotage, SNAP 340g, solvent A: Hep; solvent B: EA; gradient in %B: 3CV 30, 5CV 30 to 50, 3CV 50) to obtain 4g of yellow foam. LC-MS (A): t _R = 0.87 min; [M+H] ⁺ : 426.0.

1.4. (S)-4-(4-carboxy-2-trifluoromethyl-thiazol-5-yl)-2-hydroxymethyl-hexahydropyridine

Tert-Butyl-1-carboxylate

To a solution of intermediate 1.3 (3.96 g) in EtOH (20 mL) was added 1M NaOH (20 mL) at room temperature, and the reaction mixture was stirred for 1 hour and 10 minutes. The solvent was evaporated and the residue was acidified to pH 2-3 by adding aqueous citric acid solution (10%). The aqueous layer was extracted with DCM (3×), and the combined organic layers were dried over MgSO ₄ and concentrated to dryness to obtain 2.89 g of material as a beige solid. LC-MS (A): t _R = 0.79 min; [M+H] ⁺ : 412.1.

1.5. (S)-4-(4-Bromo-2-trifluoromethyl-thiazol-5-yl)-2-hydroxymethyl-hexahydropyridine

Tert-Butyl-1-carboxylate

To a solution of intermediate 1.4 (2.88 g) in THF (55 mL) at room temperature, LiBr (614 mg) and (di(acetyloxy)iodo)benzene (2.3 g) were added. The resulting suspension was stirred overnight at room temperature. The reaction mixture was evaporated and the residue was dissolved with H ₂ O/DCM and extracted with DCM (3×). The combined organic layer was dried over MgSO ₄ , filtered off and evaporated to dryness. The crude product was purified by CC (Biotage, SNAP 100g cartridge, solvent A: Hep; solvent B: EA; gradient in %B: 10 for 5CV, 5CV 10 to 30, 40 for 3CV) to obtain 2.5g as white Solid material. LC-MS (A): t _R = 0.93 min; [M+H] ⁺ : 445.9.

1.6. (S)-2-Hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

Tert-Butyl-1-carboxylate

酸(1.65g)、Pd(PPh₃)₂Cl₂(202mg)、1M Na₂CO₃(15mL)於MeCN(15mL)中之混合物20小時。使反應混合物冷卻至室溫，用H₂O稀釋且用DCM(3×)萃取。將經合併之有機層經MgSO₄乾燥，過濾出且蒸發至乾燥。藉由CC(Biotage，SNAP 340g筒，溶劑A：Hep；溶劑B： EA；以%B計之梯度：10持續5CV，歷經6CV 10至30，30持續3CV)純化粗產物，獲得2.22g呈黃色泡沫狀之物質。LC-MS(A)：t_R=0.98min；[M+H]⁺：513.9。 Stir the intermediate 1.5 (2.3g), 2-(trifluoromethyl)pyrimidine-5- vigorously under argon at 80°C

A mixture of acid (1.65 g), Pd(PPh ₃ ) ₂ Cl ₂ (202 mg), 1M Na ₂ CO ₃ (15 mL) in MeCN (15 mL) for 20 hours. The reaction mixture was cooled to room temperature, diluted with H ₂ O and extracted with DCM (3×). The combined organic layer was dried over MgSO ₄ , filtered off and evaporated to dryness. The crude product was purified by CC (Biotage, SNAP 340g cartridge, solvent A: Hep; solvent B: EA; gradient in %B: 10 for 5CV over 6CV 10 to 30, 30 for 3CV) to obtain 2.22g as yellow Foamy substance. LC-MS (A): t _R = 0.98 min; [M+H] ⁺ : 513.9.

1.7. {(S)-4-[2-Trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-2-yl}-methanol; in the form of hydrochloride

A mixture of intermediate 1.6 (2.25 g) in HCl (22 mL, 4M in dioxane) was stirred at room temperature for 1 hour. The reaction mixture was evaporated and dried under high vacuum to give 2.18 g of material as a brown foam. LC-MS (A): t _R =0.67 min; [M+H ⁺ +CH ₃ CN] ⁺ : 413.2.

1.8. (3-tert-butyl-[1,2,4]triazol-1-yl)-benzyl acetate

To a solution of 3-tert-butyl-1H-1,2,4-triazole (225 mg) in MeCN (12 mL) was added Cs ₂ CO ₃ (586 mg), followed by benzyl bromoacetate (0.29 mL) , And the mixture was stirred at room temperature for 1 hour and 45 minutes. The reaction mixture was diluted with EA and washed with water (2X) and brine. The aqueous layer was extracted with EA (2×), and the combined organic layers were dried over MgSO ₄ , filtered off and evaporated to dryness. The residue was purified by CC (Biotage, SNAP 25g cartridge, solvent A: DCM; solvent B: DCM/MeOH 8: 2; gradient in %B: 15 for 8 CV) to obtain 216 mg of the substance as a light yellow solid ( Single site isomer). LC-MS (A): t _R = 0.73 min; [M+H] ⁺ : 274.1.

1.9. (3-tert-butyl-[1,2,4]triazol-1-yl)-acetic acid

The flask containing intermediate 1.8 (202 mg), Pd/C (39 mg) in EtOH (2 mL) was evacuated and backfilled with argon (3×), then evacuated and backfilled with H ₂ (3×), and at room temperature The reaction mixture was stirred for 2 hours. The reaction mixture was filtered on a plug of diatomaceous earth, and the filtrate was evaporated to dryness to obtain 130 mg of a white solid. LC-MS (A): t _R = 0.36 min; [M+H] ⁺ : 184.3.

1.10. 2-(3-tert-butyl-[1,2,4]triazol-1-yl)-1-{(S)-2-hydroxymethyl-4-[2-trifluoromethyl- 4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone

A mixture of Intermediate 1.7 (30 mg), Intermediate 1.9 (11 mg), HATU (26 mg) and NEt ₃ (26 μL) in DCM (1.5 μL) was stirred at room temperature overnight. The reaction mixture was evaporated to dryness, and the crude product was purified by preparative LC-MS (IV) to obtain 6 mg of the substance as a white solid. LC-MS (C): t _R = 1.12 min; [M+H] ⁺ : 579.2.

Example 2: 2-(3,5-dimethyl-[1,2,4]triazol-1-yl)-1-{(S)-2-hydroxymethyl-4-[2-trifluoromethyl Yl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone

To a solution of intermediate 1.7 (2.15 g) in DCM (66 mL) was added (3,5-dimethyl-1H-1,2,4-triazol-1-yl)acetic acid (743 mg) at room temperature , DIPEA (2.05 mL) and HATU (2.37 g), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with DCM and washed with 1M NaHSO ₄ , saturated aqueous NaHCO ₃ and brine. The aqueous layer was extracted with 2×DCM and the combined organic layers were dried over MgSO ₄ , filtered off and evaporated to dryness. By CC (Biotage, SNAP 100g cartridge, solvent A: DCM; solvent B: DCM/MeOH 8: 2+0.1% Et ₃ N; gradient in %B: 15 for 5CV, after 3CV 15 to 25, 25 for 5CV) purification. The residual DIPEA in the product was removed by extraction in DCM/H ₂ O to obtain 778 mg of the substance as a white solid.

LC-MS (C): t _R = 0.97 min; [M+H] ⁺ : 551.1.

Example 3: 2-(3-cyclopropyl-[1,2,4]triazol-1-yl)-1-{(S)-2-hydroxymethyl-4-[2-trifluoromethyl- 4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone 3.1. (3-Cyclopropyl-[1,2,4]triazol-1-yl)-benzyl acetate

To a solution of 3-cyclopropyl-1H-1,2,4-triazole (500 mg) in THF (10 mL) was added NaH (60% in oil, 174 mg) at 0°C, and the mixture was stirred for 5 minute. Then benzyl bromoacetate (0.719 mL) was added and the reaction mixture was stirred at 0 °C for 45 minutes. The mixture was quenched with saturated aqueous NH ₄ Cl and the aqueous layer was extracted with EA (3×). The combined organic layer was dried over MgSO ₄ , filtered off and evaporated to dryness. Purification by CC (Biotage, SNAP 25g cartridge, solvent A: DCM; solvent B: MeOH; gradient in %B: 1 for 4CV over 10CV 1 to 10, 10 for 2CV) yielded 831 mg of regioisomer The substance of the mixture. By preparative separation of palm HPLC (II), two regioisomers were obtained:

The first dissociated part: (5-cyclopropyl-[1,2,4]triazol-1-yl)-benzyl acetate. LC-MS (A): t _R =0.75 min; [M+H] ⁺ : 258.1. A Roesy signal can be seen between 5.04 ppm of CH ₂ CO ₂ and 1.74 ppm of CH (cyclopropyl).

The second dissociated part: (3-cyclopropyl-[1,2,4]triazol-1-yl)-benzyl acetate. LC-MS (A): t _R =0.75 min; [M+H] ⁺ ; 258.1. The Roesy signal can be seen between 4.94 ppm of CH ₂ CO ₂ and 8.08 ppm of CH (triazole).

3.2. (3-Cyclopropyl-[1,2,4]triazol-1-yl)-acetic acid

This was prepared using a method similar to Example 1, step 1.9, replacing intermediate 1.8 with intermediate 3.1 ((3-cyclopropyl-[1,2,4]triazol-1-yl)-benzyl acetate) Compound. LC-MS (A): t _R = 0.33 min; [M+H] ⁺ : 168.47.

3.3. 2-(3-Cyclopropyl-[1,2,4]triazol-1-yl)-1-{(S)-2-hydroxymethyl-4-[2-trifluoromethyl-4 -(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone

This compound was prepared using a method similar to Example 1, Step 1.10, replacing Intermediate 1.9 with Intermediate 3.2. The crude product was purified by preparative LC-MS (IV). LC-MS (C): t _R = 1.05 min; [M+H] ⁺ : 563.1.

Example 4: 1-{(S)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]- Hexahydropyridine

-1-yl}-2-(3-isopropyl-[1,2,4]triazol-1-yl)-ethanone 4.1. (3-isopropyl-[1,2,4]triazol-1-yl)-benzyl acetate

This compound was prepared using a method similar to Example 1, Step 1.8, replacing 3-tributyl-1H-1,2,4-triazole with 3-isopropyl-1H-1,2,4-triazole . The regioisomer mixture was purified by preparative palmitic HPLC (III). The first dissociated part: (3-isopropyl-[1,2,4]triazol-1-yl)-benzyl acetate. LC-MS (A): t _R =0.76 min; [M+H] ⁺ : 260.2. A Roesy signal can be seen between CH ₂ at 4.96 ppm and CH (triazole) at 8.08 ppm.

The second dissociated part: (5-isopropyl-[1,2,4]triazol-1-yl)-benzyl acetate. LC-MS (A): t _R =0.76 min; [M+H] ⁺ : 260.2. 4.96ppm in the visible Roesy CH ₂ 2.97ppm signals between the CH (isopropyl) and.

4.2. (3-isopropyl-[1,2,4]triazol-1-yl)-acetic acid

This compound was prepared using a method similar to Example 1, step 1.9, replacing (intermediate 1.8) with (3-isopropyl-[1,2,4]triazol-1-yl)-benzyl acetate from step 4.1 . LC-MS (A): t _R = 0.30 min; [M+H] ⁺ : 170.2.

4.3. 1-{(S)-2-Hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexa Hydropyridine

-1-yl}-2-(3-isopropyl-[1,2,4]triazol-1-yl)-ethanone

This compound was prepared using a method similar to Example 1, Step 1.10, replacing Intermediate 1.9 with Intermediate 4.2. The crude product was purified by preparative LC-MS (IV). LC-MS (C): t _R = 1.07 min; [M+H] ⁺ : 564.9.

Example 5: 1-{(S)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]- Hexahydropyridine

-1-yl}-2-(3-trifluoromethyl-[1,2,4]triazol-1-yl)-ethanone 5.1. (3-Trifluoromethyl-[1,2,4]triazol-1-yl)-benzyl acetate

Using a method similar to Example 1, Step 1.8, replace 3-tributyl-1H-1,2,4-triazole with 3-(trifluoromethyl)-1H-1,2,4-triazole Prepare this compound. After CC, the desired compound is obtained in the form of a single regioisomer. LC-MS (A): t _R = 0.85 min; [M+H] ⁺ : 286.1.

5.2. (3-Trifluoromethyl-[1,2,4]triazol-1-yl)-acetic acid

This compound was prepared using a method similar to Example 1, step 1.9, replacing intermediate 1.8 with intermediate 5.1. LC-MS (A): t _R = 0.42 min; [M+H] ⁺ : 196.1.

5.3. 1-{(S)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexa Hydropyridine

-1-yl}-2-(3-trifluoromethyl-[1,2,4]triazol-1-yl)-ethanone

This compound was prepared using a method similar to Example 1, step 1.10, replacing intermediate 1.9 with intermediate 5.2. Additional 1.1 eq HATU and 1 eq intermediate 5.2 were added and the reaction mixture was stirred for another 24 hours. The crude product was purified by preparative LC-MS (IV). LC-MS (C): t _R = 1.15 min; [M+H] ⁺ : 591.1.

Example 6: 1-{(S)-4-[4-(2-ethoxy-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-hydroxymethyl-hexa Hydropyridine

-1-yl}-2-(3-trifluoromethyl-[1,2,4]triazol-1-yl)-ethanone 6.1. (S)-4-[4-(2-ethoxy-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-hydroxymethyl-hexahydropyridine

Tert-Butyl-1-carboxylate

酸替換2-(三氟甲基)嘧啶-5-

酸來製備此化合物。LC-MS(A)：t_R=0.92min；[M+H]⁺：490.2。 Using a method similar to Example 1, step 1.6, using 2-ethoxypyrimidine-5-

Acid replacement of 2-(trifluoromethyl)pyrimidine-5-

Acid to prepare this compound. LC-MS (A): t _R = 0.92 min; [M+H] ⁺ : 490.2.

6.2. (S)-(4-(4-(2-ethoxypyrimidin-5-yl)-2-(trifluoromethyl)thiazol-5-yl)hexahydropyridine

-2-yl) methanol in the form of hydrochloride

This compound was prepared using a method similar to Example 1, step 1.7, replacing intermediate 1.6 with intermediate 6.1. LC-MS (A): t _R =0.57 min; [M+H] ⁺ : 390.2.

6.3. 1-{(S)-4-[4-(2-ethoxy-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-hydroxymethyl-hexahydro Pyridine

-1-yl}-2-(3-trifluoromethyl-[1,2,4]triazol-1-yl)-ethanone

This compound was prepared using a method similar to Example 1, step 1.10, replacing intermediate 1.7 with intermediate 6.2, intermediate 1.9 with intermediate 5.2, and DCM with DMF. The crude product was purified by preparative LC-MS (I). LC-MS (C): t _R = 1.09 min; [M+H] ⁺ : 567.1.

Example 7: 2-(3,5-dimethyl-[1,2,4]triazol-1-yl)-1-{(S)-4-[4-(2-ethoxy-pyrimidine- 5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-hydroxymethyl-hexahydropyridine

-1-yl}-ethanone

This compound was prepared using a method similar to Example 6, step 6.3, replacing the intermediate 5.2 with 3,5-dimethyl-1H-1,2,4-triazol-1-yl)acetic acid. The crude product was purified by preparative LC-MS (I). LC-MS (B): t _R = 1.28 min; [M+H] ⁺ : 527.2.

Example 8: 1-{(S)-4-[4-(2-cyclopropyl-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-hydroxymethyl-hexa Hydropyridine

-1-yl}-2-(3,5-dimethyl-[1,2,4]triazol-1-yl)-ethanone 8.1. (S)-4-[4-(2-Cyclopropyl-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-hydroxymethyl- hexahydropyridine

Tert-Butyl-1-carboxylate

-2-基)嘧啶替換2-(三氟甲基)嘧啶-5-

酸來製備此化合物。LC-MS(A)：t_R=0.92min；[M+H]⁺：486.2。 Use a method similar to Example 1 and step 1.6, using 2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxane

-2-yl)pyrimidine instead of 2-(trifluoromethyl)pyrimidine-5-

Acid to prepare this compound. LC-MS (A): t _R = 0.92 min; [M+H] ⁺ : 486.2.

8.2. (S)-(4-(4-(2-Cyclopropylpyrimidin-5-yl)-2-(trifluoromethyl)thiazol-5-yl)hexahydropyridine

-2-yl) methanol in the form of hydrochloride

This compound was prepared using a method similar to Example 1, step 1.7, and replacing intermediate 1.6 with intermediate 8.1. LC-MS (A): t _R =0.57 min; [M+H] ⁺ : 386.1.

8.3. 1-{(S)-4-[4-(2-Cyclopropyl-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-hydroxymethyl-hexahydro Pyridine

-1-yl}-2-(3,5-dimethyl-[1,2,4]triazol-1-yl)-ethanone

This compound was prepared using a method similar to Example 7 and replacing intermediate 6.2 with intermediate 8.2. The crude product was purified by preparative LC-MS (I). LC-MS (C): t _R =0.9 min; [M+H] ⁺ : 523.2.

Example 9: 1-{(S)-4-[4-(2-cyclopropyl-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-hydroxymethyl-hexa Hydropyridine

-1-yl}-2-(3-trifluoromethyl-[1,2,4]triazol-1-yl)-ethanone

This compound was prepared using a method similar to Example 8, step 8.3, replacing (3,5-dimethyl-1H-1,2,4-triazol-1-yl)acetic acid with intermediate 5.2. The crude product was purified by preparative LC-MS (I) followed by preparative TLC (DCM/MeOH 97:3). LC-MS (C): t _R =1.1 min; [M+H] ⁺ : 563.1.

Example 10: 1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(6-trifluoromethyl-pyridin-3-yl)-thiazol-5-yl]- Hexahydropyridine

-1-yl}-2-(3-isopropyl-[1,2,4]triazol-1-yl)-ethanone 10.1. (R)-4-(4-Bromo-2-trifluoromethyl-thiazol-5-yl)-2-hydroxymethyl-hexahydropyridine

Tert-Butyl-1-carboxylate

替換步驟1.3中之(S)-1-Boc-2-羥甲基六氫吡

來製備此化合物。LC-MS(A)：t_R=0.92min；[M+H]⁺：445.9。 Using a method similar to Example 1, following steps 1.1 to 1.5, using (R)-1-Boc-2-hydroxymethylhexahydropyridine

Replace (S)-1-Boc-2-hydroxymethylhexahydropyridine in step 1.3

To prepare this compound. LC-MS (A): t _R = 0.92 min; [M+H] ⁺ : 445.9.

10.2. (R)-2-Hydroxymethyl-4-[2-trifluoromethyl-4-(6-trifluoromethyl-pyridin-3-yl)-thiazol-5-yl]-hexahydropyridine

Tert-Butyl-1-carboxylate

酸替換2-(三氟甲基)嘧啶-5-

酸來製備此化合物。LC-MS(A)：t_R=0.99min；[M+H]⁺：512.9。 Using a method similar to Example 1, step 1.6, using 2-(trifluoromethyl)pyridine-5-

Acid replacement of 2-(trifluoromethyl)pyrimidine-5-

Acid to prepare this compound. LC-MS (A): t _R =0.99 min; [M+H] ⁺ : 512.9.

10.3. (R)-(4-(2-(Trifluoromethyl)-4-(6-(trifluoromethyl)pyridin-3-yl)thiazol-5-yl)hexahydropyridine

-2-yl) methanol in the form of hydrochloride

This compound was prepared using a method similar to Example 1, step 1.7, and replacing intermediate 1.6 with intermediate 10.2. LC-MS (A): t _R =0.68 min; [M+H] ⁺ : 413.1.

10.4. 1-{(R)-2-Hydroxymethyl-4-[2-trifluoromethyl-4-(6-trifluoromethyl-pyridin-3-yl)-thiazol-5-yl]-hexa Hydropyridine

-1-yl}-2-(3-isopropyl-[1,2,4]triazol-1-yl)-ethanone

This compound was prepared using a method similar to Example 4, step 4.3, replacing intermediate 1.7 with intermediate 10.3 and DCM with DMF. The crude product was purified by preparative LC-MS (I). LC-MS (C): t _R =1.1 min; [M+H] ⁺ : 564.2.

Example 11: 1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]- Hexahydropyridine

-1-yl}-2-(3-isopropyl-[1,2,4]triazol-1-yl)-ethanone 11.1. (R)-2-Hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

Tert-Butyl-1-carboxylate

酸替換2-(三氟甲基)吡啶-5-

酸來製備此化合物。LC-MS(A)：t_R=0.98min；[M+H]⁺：513.9。 Using a method similar to Example 10, Step 10.2, using 2-(trifluoromethyl)pyrimidine-5-

Acid replacement 2-(trifluoromethyl)pyridine-5-

Acid to prepare this compound. LC-MS (A): t _R = 0.98 min; [M+H] ⁺ : 513.9.

11.2. (R)-(4-(2-(Trifluoromethyl)-4-(2-(trifluoromethyl)pyrimidin-5-yl)thiazol-5-yl)hexahydropyridine

-2-yl) methanol in the form of hydrochloride

This compound was prepared using a method similar to Example 10, step 10.3, and replacing intermediate 10.2 with intermediate 11.1. LC-MS (A): t _R =0.67 min; [M+H] ⁺ : 414.0.

11.3. 1-{(R)-2-Hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol- 5-yl]-hexa Hydropyridine

-1-yl}-2-(3-isopropyl-[1,2,4]triazol-1-yl)-ethanone

This compound was prepared using a method similar to Example 10, step 10.4, and replacing intermediate 10.3 with intermediate 11.2. The crude product was purified by preparative LC-MS (I). LC-MS (C): t _R = 1.07 min; [M+H] ⁺ : 565.4.

Example 12: 2-(3,5-dimethyl-[1,2,4]triazol-1-yl)-1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl Yl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone

This compound was prepared using a method similar to Example 11, step 11.3, replacing (intermediate 4.2) with (3,5-dimethyl-1H-1,2,4-triazol-1-yl)acetic acid. The crude product was purified by preparative LC-MS (II). LC-MS (C): t _R = 0.97 min; [M+H] ⁺ : 551.1.

Example 13: 2-Benzimidazol-1-yl-1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidine-5- Group)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone

This compound was prepared using a method similar to Example 11, Step 11.3, replacing 2-Intermediate 4.2 with 2-(1H-benzimidazol-1-yl)acetic acid. The crude product was purified by preparative LC-MS (I). LC-MS (C): t _R = 0.89 min; [M+H] ⁺ : 572.1.

Example 14: 2-(5-fluoro-indol-1-yl)-1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl -Pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone

This compound was prepared using a method similar to Example 11, step 11.3, replacing (intermediate 4.2) with (5-fluoroindol-1-yl)acetic acid. The crude product was purified by preparative LC-MS (V). LC-MS (C): t _R =1.25 min; [M+H] ⁺ : 589.1.

Example 15: 1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]- Hexahydropyridine

-1-yl)-2-(5-methoxy-indol-1-yl)-ethanone

This compound was prepared using a method similar to Example 11, step 11.3, replacing (intermediate 4.2) with (5-methoxy-1H-indol-1-yl)acetic acid. The crude product was purified by preparative LC-MS (I). LC-MS (C): t _R = 1.22 min; [M+H] ⁺ : 601.1.

Example 16: 1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]- Hexahydropyridine

-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone 16.1. (3-Methyl-[1,2,4]triazol-1-yl)-benzyl acetate

This compound was prepared using a method similar to Example 1, Step 1.8, replacing 3-tributyl-1H-1,2,4-triazole with 3-methyl-1H-1,2,4-triazole. The mixture of regioisomers was purified by preparative palm HPLC (IV). The first dissociated part: (5-methyl-[1,2,4]triazol-1-yl)-benzyl acetate. LC-MS (A): t _R = 0.68 min; [M+H] ⁺ : 232.16. ¹ H-NMR (CDCl ₃ ): 7.83 (s, 1H); 7.40-7.33 (m, 5H); 5.23 (s, 2H); 4.93 (s, 2H); 2.43 (s, 3H). A Roesy signal can be seen between CH ₂ at 4.93 ppm and CH ₃ at 2.43 ppm.

The second dissociated part: (3-methyl-[1,2,4]triazol-1-yl)-benzyl acetate. LC-MS (A): t _R = 0.67 min; [M+H] ⁺ : 232.16. ¹ H-NMR (CDCl ₃ ): 8.05 (s, 1H); 7.40-7.30 (m, 5H); 5.23 (s, 0.95H, CH ₂ ); 4.93-4.88 (3s, 2H); 2.42 (s, 3H ). A Roesy signal can be seen between 8.05 ppm of CH (triazole) and 4.93-4.88 ppm of CH ₂ .

16.2. (3-Methyl-[1,2,4]triazol-1-yl)-acetic acid

This compound was prepared using a method similar to Example 1, step 1.9, replacing (intermediate 1.8) with (3-methyl-[1,2,4]triazol-1-yl)-benzyl acetate from step 16.1. LC-MS (A): t _R =0.18 min; [M+H] ⁺ :142.22.

16.3. 1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexa Hydropyridine

-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone

This compound was prepared using a method similar to Example 11, step 11.3, and replacing intermediate 4.2 with intermediate 16.2. The crude product was purified by preparative LC-MS (II). LC-MS (B): t _R = 1.35 min; [M+H] ⁺ : 537.1.

Example 17: 1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]- Hexahydropyridine

-1-yl}-2-(3-methoxymethyl-[1,2,4]triazol-1-yl)-ethanone 17.1. (3-Methoxymethyl-[1,2,4]triazol-1-yl)-benzyl acetate

Using a method similar to Example 1, step 1.8, using 3-(methoxymethyl)-1H-1,2,4- This compound was prepared by replacing 3-tributyl-1H-1,2,4-triazole with triazole. With two CCs (1. Biotage, SNAP 10g cartridge, solvent A: DCM; solvent B: DCM/MeOH 8: 2; gradient in %B: 5 for 7 CV, 3CV 5 to 15, 15 for 3 CV. 2. Biotage, SNAP 10g cartridge, solvent A: DCM; solvent B: DCM/MeOH 8: 2; gradient in %B: 5 for 5CV, 3CV 5 to 10, 10 for 3CV, 10 to 15 for 3 CV ) Purification of the crude product yields two regioisomers:

The first dissociated part: (5-methoxymethyl-[1,2,4]triazol-1-yl)-benzyl acetate: colorless oil. LC-MS (A): t _R = 0.71 min; [M+H] ⁺ : 262.2.

The second dissociated part: (3-methoxymethyl-[1,2,4]triazol-1-yl)-benzyl acetate: colorless oil. LC-MS (A): t _R =0.67 min; [M+H] ⁺ : 262.1. The Roesy signal can be seen between 8.17 ppm of CH (triazole) and 5.01 ppm of NCH ₂ CO ₂ .

17.2. (3-Methoxymethyl-[1,2,4]triazol-1-yl)-acetic acid

Prepared using a method similar to Example 1, step 1.9, replacing (intermediate 1.8) with (3-methoxymethyl-[1,2,4]triazol-1-yl)-benzyl acetate from step 17.1 This compound. LC-MS (A): t _R = 0.24 min; [M+H] ⁺ : 172.0.

17.3. 1-{(R)-2-Hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexa Hydropyridine

-1-yl}-2-(3-methoxymethyl-[1,2,4]triazol-1-yl)-ethanone

This compound was prepared using a method similar to Example 11, step 11.3, and replacing intermediate 4.2 with intermediate 17.2. The crude product was purified by preparative LC-MS (II). LC-MS (B): t _R = 1.36 min; [M+H] ⁺ : 567.1.

Example 18: 1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]- Hexahydropyridine

-1-yl}-2-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-[1,2,4]triazol-1-yl]-ethanone 18.1. 5-Methyl-3-(1H-[1,2,4]triazol-3-yl)-[1,2,4]oxadiazole

To a suspension of N-hydroxy-acetamidine (803 mg) in THF (25 mL) was added NaH (60% in oil, 434 mg) at room temperature. The foaming suspension was stirred at 70°C under argon for 30 minutes, then 1H-1,2,4-triazole-3-carboxylic acid methyl ester (725 mg) was added and the mixture was stirred at 70°C for 2 hours and 40 minutes . The reaction mixture was cooled to room temperature, quenched with saturated NH ₄ Cl, filtered, and the precipitate was washed with THF and MeOH. The filtrate was evaporated and dried under high vacuum to obtain 1.85 g of material as a beige solid. LC-MS (A): t _R = 0.4 min; [M+H] ⁺ : 152.2.

18.2. [3-(5-Methyl-[1,2,4]oxadiazol-3-yl)-[1,2,4]triazol-1-yl]-benzyl acetate

To a suspension of intermediate 18.1 (1.84 g) in MeCN (85 mL) and DMF (5 mL) at room temperature was added Cs ₂ CO ₃ (3.97 g) and benzyl bromoacetate (4 mL), and at room temperature The reaction mixture was stirred overnight. The reaction mixture was evaporated to dryness, diluted with EA and washed with water (2×) and brine (1×). The aqueous layer was extracted with EA (2×). The combined organic layer was dried over MgSO ₄ , filtered off, evaporated and dried under high vacuum. CC (Biotage, SNAP 100g cartridge, solvent A: Hep; solvent B: EA; gradient in %B: 30 for 2CV, 3CV 30 to 50, 50 for 3CV, 3CV 50 to 70), and then prepare type LC -MS(I), to obtain 341 mg of the substance as a white powder (containing 22 mol% intermediate 18.3). LC-MS (A): t _R = 0.77 min; [M+H] ⁺ : 300.0.

18.3. [3-(5-Methyl-[1,2,4]oxadiazol-3-yl)-[1,2,4]triazol-1-yl]-acetate in the form of sodium salt

To a suspension of intermediate 18.2 (335 mg) in EtOH (3 mL) was added 1M NaOH (0.88 mL) at room temperature, and the resulting solution was stirred at room temperature for 1 hour. The reaction mixture was evaporated and dried under high vacuum to give 349 mg of material as a beige solid. LC-MS (A): t _R = 0.39 min; [M+H] ⁺ : 210.1.

18.4. 1-{(R)-2-Hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexa Hydropyridine

-1-yl}-2-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-[1,2,4]triazol-1-yl]-ethanone

This compound was prepared using a method similar to Example 11, step 11.3, and replacing intermediate 4.2 with intermediate 18.3. The crude product was purified by preparative LC-MS (I). LC-MS (B): t _R = 1.41 min; [M+H] ⁺ : 605.1.

Example 19: 1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]- Hexahydropyridine

-1-yl}-2-(3-phenyl-[1,2,4]triazol-1-yl)-ethanone

This compound was prepared using a method similar to Example 11, step 11.3, and replacing intermediate 4.2 with 2-(3-phenyl-1H-1,2,4-triazol-1-yl)acetic acid. The crude product was purified by preparative LC-MS (I). LC-MS (C): t _R = 1.15 min; [M+H] ⁺ : 599.2.

Example 20: 2-(3-Acetyl-[1,2,4]triazol-1-yl)-1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl- 4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone 20.1. (3-Acetyl-[1,2,4]triazol-1-yl)-benzyl acetate

Using a method similar to Example 1, step 1.8, replace 1-tributyl-1H-1,2,4-triazole with 1-(1H-1,2,4-triazol-5-yl)ethanone To prepare this compound. By CC (Biotage, SNAP 10g cartridge, solvent A: Hep; solvent B: EA; gradient in %B: 30 for 4CV, 4CV 30 to 70, 70 for 2CV, 2CV 70 to 100, 100 for 2CV ) Purify the crude product to obtain the desired triazole regioisomer as the second dissolved fraction. A Roesy signal can be seen between 8.28 ppm CH (triazole) and 5.1 ppm CH ₂ .

LC-MS (A): t _R =0.7 min; [M+H] ⁺ : 260.1.

20.2. (3-Acetyl-[1,2,4]triazol-1-yl)-acetic acid

This compound was prepared using a method similar to Example 1, Step 1.9, replacing Intermediate 1.8 with Intermediate 20.1. LC-MS (A): t _R =0.25 min; [M+H] ⁺ : 170.0.

20.3. 2-(3-Acetyl-[1,2,4]triazol-1-yl)-1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl-4 -(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone

This compound was prepared using a method similar to Example 11, step 11.3, replacing intermediate 4.2 with intermediate 20.2 and DMF with DCM. The crude product was purified by preparative LC-MS (II) followed by preparative LC-MS (IV). LC-MS (B): t _R = 1.38 min; [M+H] ⁺ : 565.1.

Example 21: 2-[3-(1-Hydroxy-ethyl)-[1,2,4]triazol-1-yl]-1-{(R)-2-hydroxymethyl-4-[2- Trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone

To a solution of Example 20 (40 mg) in THF (0.75 mL) and EtOH (0.25 mL) was added NaBH ₄ (1.3 mg), and the mixture was stirred at 0° C. for 1 hour and 10 minutes. The reaction mixture was quenched by the addition of H ₂ O and extracted with DCM (3×). The combined organic layer was evaporated and dried under high vacuum. The crude product was purified by preparative LC-MS (IV) to obtain 25 mg of the substance as a white powder. LC-MS (B): t _R = 1.32 min; [M+H] ⁺ : 567.1.

Example 22: 1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]- Hexahydropyridine

-1-yl)-2-(3-methyl-pyrazol-1-yl)-ethanone

This compound was prepared using a method similar to Example 11, step 11.3, substituting (3-methyl-1H-pyrazol-1-yl)acetic acid for intermediate 4.2 and DCM for DMF. The crude product was purified by preparative LC-MS (IV). LC-MS (C): t _R = 1.07 min; [M+H] ⁺ : 536.4.

Example 23: 1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]- Hexahydropyridine

-1-yl}-2-(3-pyridin-2-yl-[1,2,4]triazol-1-yl)-ethanone 23.1. (3-pyridin-2-yl-[1,2,4]triazol-1-yl)-acetic acid tert-butyl ester

Using a method similar to Example 1, Step 1.8, replace 3-tert-butyl-1H-1,2,4-triazole with 2-(1H-1,2,4-triazol-3-yl)pyridine and This compound was prepared by replacing benzyl bromoacetate with tert-butyl bromoacetate. The compound was further purified by preparative LC-MS (VI). LC-MS (A): t _R = 0.61 min; [M+H] ⁺ : 261.2.

23.2. 2-(3-(pyridin-2-yl)-1H-1,2,4-triazol-1-yl)acetic acid, in the form of the hydrochloride salt

To a suspension of intermediate 23.1 (263 mg) in dioxane (2 mL) was added HCl (4M in dioxane; 2 mL). After 1 hour at room temperature, a few drops of H ₂ O were added and the reaction mixture was stirred for 26 hours. The reaction mixture was evaporated and dried under high vacuum to obtain 263 mg of the substance as a light yellow solid. LC-MS (A): t _R = 0.29 min; [M+H] ⁺ : 205.1.

23.3. 1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexa Hydropyridine

-1-yl}-2-(3-pyridin-2-yl-[1,2,4]triazol-1-yl)-ethanone

This compound was prepared using a method similar to Example 11, step 11.3, replacing intermediate 4.2 with intermediate 23.2 and DMF with DCM. The crude product was purified by preparative LC-MS (IV) followed by preparative TLC (0.5 mm, DCM/MeOH 95/5). LC-MS (C): t _R =1.00 min; [M+H] ⁺ : 600.1.

Example 24 and Example 25: 2-(3-ethyl-5-methyl-[1,2,4]triazol-1-yl)-1-{(R)-2-hydroxymethyl-4-[ 2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone and 2-(5-ethyl-3-methyl-[1,2,4]triazol-1-yl)-1-{(R)-2-hydroxymethyl- 4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone

Acid precursors, examples 24 and 25:

Step 24.1. To ethyl imidate hydrochloride (500 mg) in MeCN (6 mL) was added Amberlyst A21 (1.14 g), and the suspension was stirred at room temperature for 15 minutes. The mixture was then filtered and the resin was washed with MeCN (1 mL). Acylhydrazine propionate (353 mg) was added to the filtrate, and the resulting white suspension was stirred under argon at 50°C for 4 days and at 80°C overnight. The reaction mixture was evaporated. By CC (Biotage, SNAP 10g cartridge, solvent A: DCM; solvent B: MeOH; gradient in %B: 10 for 6CV, after 3CV 10 to 20, 20 for 6CV) followed by a second CC (Biotage, SNAP 10g Cartridge, solvent A: DCM; solvent B: DCM/MeOH 8:2; gradient in %B: 25 for 7CV, 3CV 25 to 50, 50 for 5CV) purification to give 3-ethyl-5-methyl -1H-[1,2,4]triazole (125 mg of yellow oily substance). LC-MS (A): t _R = 0.21 min; [M+H] ⁺ : 112.4.

Step 24.2: Following a method similar to Example 1, Step 1.8, 3-ethyl-5-methyl-1H-[1,2,4]triazole from Step 24.1 replaces 3-tert-butyl-1H-1 , 2,4-triazole. Obtain a mixture of regioisomers: (3-ethyl-5-methyl-[1,2,4]triazol-1-yl)-benzyl acetate and (5-ethyl-3-methyl- [1,2,4] Triazol-1-yl)-benzyl acetate.

Step 24.3: Following a method similar to Example 1, Step 1.9, the intermediate from Step 24.2 replaces the intermediate 1.8. Obtain a mixture of regioisomers (about 1:1): (3-ethyl-5-methyl-[1,2,4]triazol-1-yl)-acetic acid and (5-ethyl-3- Methyl-[1,2,4]triazol-1-yl)-acetic acid.

The final compound was prepared using a method similar to Example 11, step 11.3, replacing intermediate 4.2 with intermediate from step 24.3 and DMF with DCM. The crude product was purified by preparative LC-MS (IV) followed by preparative paired palm HPLC (I). The two portions were dissolved in DCM and washed with water (2×), and the aqueous layer was extracted with DCM (1×). The combined organic layer was dried over MgSO ₄ , filtered off, evaporated and dried under high vacuum.

-1-基}-乙酮。LC-MS(C)：t_R=1.00min；[M+H]⁺：565.1。 First dissociation part (Example 24): 2-(3-ethyl-5-methyl-[1,2,4]triazol-1-yl)-1-{(R)-2-hydroxymethyl- 4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone. LC-MS (C): t _R =1.00 min; [M+H] ⁺ : 565.1.

-1-基}-乙酮。LC-MS(C)：t_R=1.00min；[M+H]⁺：565.5。 Second dissociation moiety (Example 25): 2-(5-ethyl-3-methyl-[1,2,4]triazol-1-yl)-1-{(R)-2-hydroxymethyl- 4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone. LC-MS (C): t _R =1.00 min; [M+H] ⁺ : 565.5.

Example 26: 1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]- Hexahydropyridine

-1-yl}-2-imidazo[4,5-b]pyridin-3-yl-ethanone 26.1. imidazo[4,5-b]pyridin-3-yl-benzyl acetate

To a solution of 4-azabenzimidazole (4.75 g) in DMF (80 mL) was added benzyl bromoacetate (6.58 mL), followed by Cs ₂ CO ₃ (25.9 g). The resulting suspension was stirred overnight. The reaction mixture was diluted with EA and washed with water (2×) and saturated aqueous NH ₄ Cl. The aqueous layer was extracted with EA (2×). The combined organic layer was dried over MgSO ₄ , filtered off and evaporated under reduced pressure. By CC (Biotage, SNAP 100g cartridge, solvent A: DCM; solvent B: DCM/MeOH 8: 2; gradient in %B: 3CV 0 to 5, 5 for 5CV, 5CV 5 to 15, 15 for 3CV) The crude product was purified to obtain 4.99 g of the desired compound as a yellow solid. LC-MS (B): t _R = 0.59 min; [M+H] ⁺ : 267.86.

26.2. imidazo[4,5-b]pyridin-3-yl-acetic acid

To a yellow suspension of intermediate 26.1 (4.99 g) in MeOH (30 mL) and acetic acid (0.3 mL) was added Pd/C (10%, 994 mg) under argon. The flask was evacuated and backfilled three times with argon, then evacuated and backfilled twice with hydrogen. The reaction mixture was stirred under hydrogen at room temperature for 5 hours, filtered on celite and washed with MeOH. The filtrate was evaporated to dryness to obtain 2.41 g of off-white solid, which was used without purification. LC-MS (B): t _R =0.15 min; [M+H] ⁺ : 178.24.

26.3. 1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexa Hydropyridine

-1-yl}-2-imidazo[4,5-b]pyridin-3-yl-ethanone

This compound was prepared using a method similar to Example 11, step 11.3, replacing intermediate 4.2 with intermediate 26.2 and DMF with DCM. The crude product was purified by preparative LC-MS (IV) followed by preparative TLC (0.5 mm, DCM/MeOH 95/5). LC-MS (A): t _R = 0.8 min; [M+H] ⁺ : 573.0.

Example 27: 2-(3,5-dimethyl-[1,2,4]triazol-1-yl)-1-{(R)-2-(2-hydroxy-ethyl)-4-[ 2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone 27.1. (R)-2-(4-(2-(Trifluoromethyl)-4-(2-(trifluoromethyl)pyrimidin-5-yl)thiazol-5-yl)hexahydropyridine

-2-yl) ethyl-1-ol in the form of hydrochloride

替換步驟1.3中之(S)-1-第三丁氧基羰基-2-羥甲基六氫吡

來製備此化合物。LC-MS(A)：t_R=0.69min；[M+H]⁺：428.0。 Using a method similar to Example 1, following steps 1.1 to 1.7, using (R)-1-third butoxycarbonyl-2-hydroxyethylhexahydropyridine

Replace (S)-1-third butoxycarbonyl-2-hydroxymethylhexahydropyridine in step 1.3

To prepare this compound. LC-MS (A): t _R =0.69 min; [M+H] ⁺ : 428.0.

27.2. 2-(3,5-Dimethyl-[1,2,4]triazol-1-yl)-1-{(R)-2-(2-hydroxy-ethyl)-4-[2 -Trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone

This compound was prepared using a method similar to Example 12, replacing intermediate 11.2 with intermediate 27.1 and DMF with DCM. The crude product was purified by preparative LC-MS (I) followed by preparative TLC (0.5 mm, DCM/MeOH 97/3). LC-MS (C): t _R = 0.98 min; [M+H] ⁺ : 565.2.

Example 28: 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazole- 5-yl]-hexahydropyridine

-1-yl}-2-(3-trifluoromethyl-[1,2,4]triazol-1-yl)-ethanone

This compound was prepared using a method similar to Example 27, step 27.2, replacing (3,5-dimethyl-1H-1,2,4-triazol-1-yl)acetic acid with intermediate 5.2. The crude product was purified by preparative LC-MS (V). LC-MS (C): t _R = 1.16 min; [M+H] ⁺ : 605.1.

Example 29: 2-(3-cyclobutyl-[1,2,4]triazol-1-yl)-1-{(R)-2-(2-hydroxy-ethyl)-4-[2- Trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone 29.1. (3-Cyclobutyl-[1,2,4]triazol-1-yl)-benzyl acetate

This compound was prepared using a method similar to Example 1, Step 1.8, replacing 3-tributyl-1H-1,2,4-triazole with 3-cyclobutyl-1H-1,2,4-triazole . Further preparative LC-MS (IV) purification was performed, after which the regioisomeric mixture was subjected to preparative paired palm HPLC (V) for separation.

The first dissociated part: (5-cyclobutyl-[1,2,4]triazol-1-yl)-benzyl acetate. LC-MS (A): t _R =0.68 min; [M+H] ⁺ : 272.2.

The second dissociated part: (3-cyclobutyl-[1,2,4]triazol-1-yl)-benzyl acetate. LC-MS (A): t _R =0.7 min; [M+H] ⁺ : 272.2.

29.2. (3-Cyclobutyl-[1,2,4]triazol-1-yl)-acetic acid

This compound was prepared using a method similar to Example 1, step 1.9, replacing (intermediate 1.8) with (3-cyclobutyl-[1,2,4]triazol-1-yl)-benzyl acetate from step 29.1 . LC-MS (A): t _R = 0.32 min; [M+H] ⁺ : 182.3. Roesy signal can be seen between 8.40 ppm of CH (triazole) and 5.02 ppm of N- CH2- COOH.

29.3. 2-(3-Cyclobutyl-[1,2,4]triazol-1-yl)-1-{(R)-2-(2-hydroxy-ethyl)-4-[2-tri Fluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone

This compound was prepared using a method similar to Example 27, Step 27.2, replacing (3,5-dimethyl-1H-1,2,4-triazol-1-yl)acetic acid with the intermediate 29.2. The crude product was purified by preparative LC-MS (IV). LC-MS (C): t _R = 1.11 min; [M+H] ⁺ : 591.2.

Example 30: 2-(3-tert-butyl-[1,2,4]triazol-1-yl)-1-{(R)-2-(2-hydroxy-ethyl)-4-[2 -Trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone

This compound was prepared using a method similar to Example 27, step 27.2, replacing (3,5-dimethyl-1H-1,2,4-triazol-1-yl)acetic acid with intermediate 1.9. The crude product was purified by preparative LC-MS (I). LC-MS (C): t _R = 1.13 min; [M+H] ⁺ : 593.2.

Example 31: 2-(3-cyclopropyl-[1,2,4]triazol-1-yl)-1-{(R)-2-(2-hydroxy-ethyl)-4-[2- Trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone

This compound was prepared using a method similar to Example 27, step 27.2, replacing (3,5-dimethyl-1H-1,2,4-triazol-1-yl)acetic acid with intermediate 3.2. The crude product was purified by preparative LC-MS (I). LC-MS (C): t _R = 1.06 min; [M+H] ⁺ : 577.4.

Example 32: 2-(3-ethyl-[1,2,4]triazol-1-yl)-1-{(R)-2-(2-hydroxy-ethyl)-4-[2-tri Fluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone 32.1. (3-ethyl-[1,2,4]triazol-1-yl)-benzyl acetate

This compound was prepared using a method similar to Example 1, Step 1.8, replacing 3-tributyl-1H-1,2,4-triazole with 3-ethyl-1H-1,2,4-triazole. The regioisomer mixture was purified by preparative palm HPLC (VI). The first dissociated part: (5-ethyl-[1,2,4]triazol-1-yl)-benzyl acetate: LC-MS (A): t _R =0.72 min; [M+H] ⁺ : 246.2. The Roesy signal can be seen between 2.72 ppm CH ₂ CH ₃ and 4.93 ppm CH ₂ CO ₂ .

Second dissociated fraction: (3-ethyl-[1,2,4]triazol-1-yl)-benzyl acetate: LC-MS (A): t _R =0.71 min; [M+H] ⁺ : 246.2. A Roesy signal can be seen between 8.08 ppm CH and 4.96 ppm CH ₂ CO ₂ .

32.2. (3-ethyl-[1,2,4]triazol-1-yl)-acetic acid

This compound was prepared using a method similar to Example 1, step 1.9, replacing (intermediate 1.8) with (3-ethyl-[1,2,4]triazol-1-yl)-benzyl acetate from step 32.1. LC-MS (A): t _R =0.25 min; [M+H] ⁺ : 156.2.

32.3. 2-(3-ethyl-[1,2,4]triazol-1-yl)-1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoro Methyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone

This compound was prepared using a method similar to Example 27, Step 27.2, replacing (3,5-dimethyl-1H-1,2,4-triazol-1-yl)acetic acid with the intermediate 32.2. The crude product was purified by preparative LC-MS (IV). LC-MS (C): t _R = 1.04 min; [M+H] ⁺ : 564.9.

Example 33: 2-(5-ethyl-[1,2,4]triazol-1-yl)-1-{(R)-2-(2-hydroxy-ethyl)-4-[2-tri Fluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone 33.1. (5-ethyl-[1,2,4]triazol-1-yl)-acetic acid

This compound was prepared using a method similar to Example 1, step 1.9, replacing (intermediate 1.8) with (5-ethyl-[1,2,4]triazol-1-yl)-benzyl acetate from step 32.1. LC-MS (A): t _R = 0.22 min; [M+H] ⁺ : 156.1.

33.2. 2-(5-ethyl-[1,2,4]triazol-1-yl)-1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoro Methyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone

This compound was prepared using a method similar to Example 27, Step 27.2, replacing (3,5-dimethyl-1H-1,2,4-triazol-1-yl)acetic acid with the intermediate 33.1. The crude product was purified by preparative LC-MS (I). LC-MS (C): t _R = 1.03 min; [M+H] ⁺ : 565.2.

Example 34: 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazole- 5-yl]-hexahydropyridine

-1-yl}-2-(3-isopropyl-[1,2,4]triazol-1-yl)-ethanone

This compound was prepared using a method similar to Example 27, step 27.2, replacing (3,5-dimethyl-1H-1,2,4-triazol-1-yl)acetic acid with intermediate 4.2. The crude product was purified by preparative LC-MS (IV). LC-MS (C): t _R = 1.08 min; [M+H] ⁺ : 579.2.

Example 35: 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazole- 5-yl]-hexahydropyridine

-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone

This compound was prepared using a method similar to Example 27, Step 27.2, replacing (3,5-dimethyl-1H-1,2,4-triazol-1-yl)acetic acid with the intermediate 16.2. The crude product was purified by preparative LC-MS (II) followed by preparative LC-MS (IV). LC-MS (C): t _R =1.00 min; [M+H] ⁺ : 551.2.

Example 36: 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazole- 5-yl]-hexahydropyridine

-1-yl}-2-(5-methyl-[1,2,4]triazol-1-yl)-ethanone 36.1. (5-Methyl-[1,2,4]triazol-1-yl)-acetic acid

This compound was prepared using a method similar to Example 1, step 1.9, replacing (intermediate 1.8) with (5-methyl-[1,2,4]triazol-1-yl)-benzyl acetate from step 16.1. LC-MS (A): t _R =0.19 min; [M+H] ⁺ : 142.2.

36.2. 1-{(R)-2-(2-Hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazole-5 -Yl]-hexahydropyridine

-1-yl}-2-(5-methyl-[1,2,4]triazol-1-yl)-ethanone

This compound was prepared using a method similar to Example 27, Step 27.2, replacing (3,5-dimethyl-1H-1,2,4-triazol-1-yl)acetic acid with the intermediate 36.1. The crude product was purified by preparative LC-MS (IV). LC-MS (C): t _R =1.00 min; [M+H] ⁺ : 551.1.

Example 37: 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazole- 5-yl]-hexahydropyridine

-1-yl}-2-(3-methoxymethyl-[1,2,4]triazol-1-yl)-ethanone

This compound was prepared using a method similar to Example 27, Step 27.2, replacing (3,5-dimethyl-1H-1,2,4-triazol-1-yl)acetic acid with the intermediate 17.2. The crude product was purified by preparative LC-MS (IV). LC-MS (B): t _R = 1.37 min; [M+H] ⁺ : 581.1.

Example 38: 2-(3-difluoromethyl-[1,2,4]triazol-1-yl)-1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl -4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone 38.1. (3-Difluoromethyl-[1,2,4]triazol-1-yl)-benzyl acetate

Using a method similar to Example 1, step 1.8, replace 3-tributyl-1H-1,2,4-triazole with 3-(difluoromethyl)-1H-1,2,4-triazole Prepare this compound. By CC (Biotage, SNAP 50g cartridge, solvent A: Hep; solvent B: EA; gradient in %B: 30 for 5CV, over 5CV 30 to 70, 70 for 3CV, over 2CV 70 to 100, 100 for 1CV ) Purification of the crude product yields two regioisomers:

The first dissociated part: (5-difluoromethyl-[1,2,4]triazol-1-yl)-benzyl acetate: yellow oil. LC-MS (A): t _R =0.78 min; [M+H] ⁺ : 268.2.

The second dissociated part: (3-difluoromethyl-[1,2,4]triazol-1-yl)-benzyl acetate: off-white solid. LC-MS (A): t _R = 0.77 min; [M+H] ⁺ : 268.1.

38.2. (3-Difluoromethyl-[1,2,4]triazol-1-yl)-acetic acid

This was prepared using a method similar to Example 1, step 1.9, replacing (intermediate 1.8) with (3-difluoromethyl-[1,2,4]triazol-1-yl)-benzyl acetate from step 38.1 Compound. LC-MS (A): t _R = 0.26 min; [M+H] ⁺ : 178.2.

38.3. 2-(3-Difluoromethyl-[1,2,4]triazol-1-yl)-1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl- 4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone

This compound was prepared using a method similar to Example 27, Step 27.2, replacing (3,5-dimethyl-1H-1,2,4-triazol-1-yl)acetic acid with the intermediate 38.2. The crude product was purified by preparative LC-MS (IV). LC-MS (A): t _R = 0.86 min; [M+H] ⁺ : 573.0.

Example 39: 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazole- 5-yl]-hexahydropyridine

-1-yl)-2-(3-methyl-pyrazol-1-yl)-ethanone

Using a method similar to Example 27, Step 27.2, replacing (3,5-dimethyl-1H-1,2,4-triazole-1 with (3-methyl-1H-pyrazol-1-yl)acetic acid -Yl)acetic acid to prepare this compound. The crude product was purified by preparative LC-MS (IV). LC-MS (C): t _R = 1.08 min; [M+H] ⁺ : 550.0.

Example 40: 2-(3-ethyl-pyrazol-1-yl)-1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-( 2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone 40.1 (3-ethyl-pyrazol-1-yl)-benzyl acetate

This compound was prepared using a method similar to Example 1, Step 1.8, replacing 3-tributyl-1H-1,2,4-triazole with 3-ethyl-1H-pyrazole. The regioisomer mixture was purified by preparative palmitic HPLC (VII). The first dissociated part: (3-ethyl-pyrazol-1-yl)-benzyl acetate: LC-MS (A): t _R = 0.82 min; [M+H] ⁺ : 245.1. Roesy signal can be seen between 7.37 ppm of pyrazole-CH and 4.91 ppm of CH ₂ CO ₂ .

40.2 (3-ethyl-pyrazol-1-yl)-acetic acid

This compound was prepared using a method similar to Example 1 and step 1.9, replacing (intermediate 1.8) with (3-ethyl-pyrazol-1-yl)-benzyl acetate from step 40.1. LC-MS (A): t _R = 0.43 min; [M+H] ⁺ : 155.4.

40.3. 2-(3-ethyl-pyrazol-1-yl)-1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2 -Trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone

This compound was prepared using a method similar to Example 27, step 27.2, replacing (3,5-dimethyl-1H-1,2,4-triazol-1-yl)acetic acid with the intermediate 40.2. The crude product was purified by preparative LC-MS (I). LC-MS (C): t _R = 1.14 min; [M+H] ⁺ : 564.0.

Example 41: 2-(3-cyclopropyl-pyrazol-1-yl)-1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4- (2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone

Using a method similar to Example 27, Step 27.2, replacing (3,5-dimethyl-1H-1,2,4-triazole-(3-cyclopropyl-1H-pyrazol-1-yl)acetic acid 1-yl)acetic acid to prepare this compound. The crude product was purified by preparative LC-MS (IV). LC-MS (C): t _R = 1.15 min; [M+H] ⁺ : 576.2.

Example 42: 1-{(S)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]- Hexahydropyridine

-1-yl)-2-(3-methyl-pyrazol-1-yl)-ethanone

This compound was prepared using a method similar to Example 1, Step 1.10, replacing (3-methyl-1H-pyrazol-1-yl)acetic acid with intermediate 1.9. The crude product was purified by preparative LC-MS (I). LC-MS (C): t _R = 1.07 min; [M+H] ⁺ : 536.2.

Example 43: 2-(3-ethyl-pyrazol-1-yl)-1-{(S)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl -Pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone

This compound was prepared using a method similar to Example 1, Step 1.10, replacing Intermediate 1.9 with Intermediate 40.2. The crude product was purified by preparative LC-MS (I). LC-MS (C): t _R = 1.12 min; [M+H] ⁺ : 550.0.

Example 44: 2-(3-cyclopropyl-pyrazol-1-yl)-1-{(S)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoro Methyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone

This compound was prepared using a method similar to Example 1, Step 1.10, replacing (3-cyclopropyl-1H-pyrazol-1-yl)acetic acid with Intermediate 1.9. The crude product was purified by preparative LC-MS (I). LC-MS (C): t _R = 1.13 min; [M+H] ⁺ : 562.2.

II. Bioanalysis

A) FLIPR analysis: using human CXCR3A (GenBank: AY242128) engineered CHO-K1 cells coupled to G protein (Galpha(16)) in a fluorescent imaging plate reader (FLIPR: molecular device) To test the biological activity of the compound. On the day before the bioassay, cells were plated in F12 medium supplemented with 10% FBS and G418 and hygromycin antibiotics to maintain recombinant selection. In the bioassay, cells were washed and loaded with Fluo-4-AM (Invitrogen) dye in Hanks' balanced salt solution (Invitrogen) for one hour. The Hanks' balanced salt solution was used with 20 mM Hepes at pH 7.4 and 5 mM probenecid. Sodium bicarbonate (0.038%) buffer. However, this buffer without probe and containing probenecid at a concentration of 2.5 mM is also used in the washing step (wash buffer); or a buffer without both dye and probenecid but supplemented with 0.1% BSA is used for the compound Dilution step (dilution buffer). The cells were washed without excess dye, and 60 microliters of wash buffer was added. A stock solution of the test compound was prepared at a concentration of 10 mM in DMSO and serially diluted in the dilution buffer to reach the concentration required for the inhibitor amount response curve. After a 10-minute incubation period at 37°C, 10 μl of each compound dilution was transferred from the compound culture dish to the culture dish containing recombinant cells in the FLIPR instrument according to the manufacturer's instructions. After the baseline reading, the FLIPR instrument was used again, and 10 microliters of CXCL10 agonist (from Peprotech) at a concentration of 20 nM was added. Monitor the fluorescence changes before and after adding the test compound. After subtracting the baseline, output the peak emission above the reference plane after adding CXCL10.

The calculated IC ₅₀ value can vary depending on the daily analysis performance. Such fluctuations are known to those skilled in the art. In cases where the IC ₅₀ value of the same compound has been determined several times, the average value is given. The information is shown in Table 1.

B) : Receptor internalization analysis: a stock solution of the test compound was prepared at a concentration of 10 mM in DMSO and serially diluted in PBS containing 0.5% BSA to reach the concentration required for the inhibitor response curve. The diluted compound was then mixed with an equal volume of CXCL10 (Peprotech) diluted in PBS. Anticoagulated venous human whole blood was added to the mixture, which was then incubated in a CO ₂ incubator at 37°C to allow ligand-mediated receptor internalization (final CXCL10 concentration of 9 nM). After 30 minutes, blood was mixed with fluorescently labeled CXCR3 and CD4 specific antibodies (Becton Dickinson) and incubated on ice for 10 minutes. The sample was then mixed with BD FACS lysis solution (Becton Dickinson) to eliminate red blood cells. After washing the cells with PBS containing 0.5% BSA, the samples were subsequently analyzed in a flow cytometer (FACS Canto II, Becton Dickinson). For data analysis, using FACSDiva software (Becton Dickinson), the average fluorescence corresponding to the surface performance of CXCR3 cells was determined for CD4 positive cells. Using the program GraphPad (GraphPad) Prism software or the like to the data intended to a single site dose response curve and synthesis value calculation ₅₀ IC.

The calculated IC ₅₀ value can vary depending on the daily analysis performance. Such fluctuations are known to those skilled in the art. In cases where the IC ₅₀ value of the same compound has been determined several times, the average value is given. The information is shown in Table 2.

C) hERG Q-Patch analysis: For hERGK channel blocking, CHO cells that stably express the human ERG gene (registration number U04270, bSys, Witterswil, Switzerland) and QPatch automatic platform (Sophion, Ballerup, Denmark) are used in single-cell mode The compound was evaluated at room temperature. Cell cultures containing the 5% CO ₂ at 37 ℃ flask under, supplemented with 9% (v / v) fetal calf serum, 0.9% penicillin / streptomycin (10,000U / mL, Invitrogen 15140148) , 100μg / mL wet It was grown in medium (Ham's F-12 nutrient mixture, Invitrogen 21765-029) in the medium of Insulin B (Invitrogen 10687010). When the cells are ~80% confluent (every 2-3 days), they are allowed to divide for further culture or for electrophysiology. For further cultivation, the cells were detached with 0.25% trypsin EDTA solution (Invitrogen 25200-056), and a part of the cells (10-30%) were reseeded in the medium. For electrophysiology, on the experimental day, cells were separated with 0.25% trypsin EDTA solution, and all cells were suspended in suspension medium supplemented with 20 mM HEPES and 0.04 mg/mL trypsin inhibitor (293 SFM II, Invitrogen 11686- 029). The cells were kept in suspension medium at 32-35°C in QPatch automata until use, at which time an aliquot was transferred to an extracellular solution containing 0.3% v/v DMSO (in mM: NaCl 150) KCl 4; CaCl ₂ 1.2; MgCl ₂ 1; HEPES 10; adjusted to pH 7.4 with NaOH) and applied to the test plate. Use the diaphragm-voltage-clamp technique to use the internal solution in the whole cell configuration (in mM: KCl, 140; NaCl, 10; MgCl ₂ , 1; HEPES; 10; EGTA; 5; pH=7.2 at KOH) Measure K ⁺ flow. The internal Bessel filter of the QPatch automaton is used to pass the low-pass filtered flow at a cutoff frequency of 2 kHz and digitize it at 10 kHz. The holding voltage from -80mV is depolarized by 500-ms to +20mV, and then repolarized by 500-ms to -40mV to generate K ⁺ wake; the tail current amplitude is measured at the end of repolarization to -40mV. The pulse pattern was repeated every 10 seconds during the experiment, the baseline K ⁺ flow was measured after 3 minutes in the extracellular solution, and then the test solution containing the compound was applied, and the K ⁺ flow in the presence of the compound was measured 3 minutes after the application to the cells. Prepare individual test solutions by: (1) dissolving the test compound in pure DMSO, (2) diluting this DMSO solution in the extracellular solution, and (3) further adding DMSO so that the final test solution has 300 nM or 3000 nM Test compound at a concentration of 0.3% v/v DMSO. The compound action was quantified by dividing the flow in the presence of the compound by the baseline flow to block %, two or three experiments were conducted for each compound, and the final value represents the average value of the results of each experiment. The information is shown in Table 3.

Claims (21)

A compound of formula (I),

Where n represents an integer 1 or 2; X represents N or CH; R ¹ represents a heteroaryl group, wherein the heteroaryl group is 5 to 10 containing 1, 2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulfur Member monocyclic or bicyclic aromatic ring, and wherein the heteroaryl group is independently unsubstituted or mono- or di-substituted, wherein the substituent is independently selected from the group consisting of: (C _1-4 ) alkyl; C _3-6 )cycloalkyl; (C _1-4 )alkoxy; (C _1-2 )alkoxy-(C _1-2 )alkyl; (C _1-2 )alkyl-carbonyl; hydroxyl -(C _1-4 )alkyl; halogen; (C _1-2 )fluoroalkyl; phenyl; and heteroaryl, wherein the heteroaryl contains 1, 2 or 3 independently selected from oxygen and nitrogen 5 or 6 membered monocyclic aromatic ring of a hetero atom of sulfur, and wherein the heteroaryl group is independently unsubstituted or monosubstituted by (C _1-4 ) alkyl; and R ² represents (C _3-6 ) Cycloalkyl, (C _1-4 )alkoxy or (C _1-2 )fluoroalkyl; or a salt thereof. A compound as claimed in claim 1, wherein n represents an integer of 1 or 2; X represents N; R ¹ represents a 5-membered monocyclic heteroaryl group containing 2 or 3 nitrogen atoms independently mono- or di-substituted, wherein the substituent Independently selected from the group consisting of: (C _1-4 ) alkyl, (C _3-6 ) cycloalkyl, (C _1-2 ) alkoxy-(C _1-2 ) alkyl, hydroxy-( C _1-4 ) alkyl and (C _1-2 ) fluoroalkyl; or 9 members containing 1, 2 or 3 nitrogen atoms that are unsubstituted or monosubstituted by (C _1-4 ) alkoxy or halogen Bicyclic aromatic ring; and R ² represents (C _3-6 )cycloalkyl, (C _1-4 )alkoxy or trifluoromethyl; or a salt thereof. A compound according to claim 1, wherein R ¹ represents a 5-membered monocyclic heteroaryl group containing 2 or 3 nitrogen atoms which is independently mono- or di-substituted, wherein the substituent is independently selected from the group consisting of: (C _1-4 ) alkyl, (C _3-6 ) cycloalkyl and (C _1-2 ) fluoroalkyl; or salts thereof. The compound according to any one of claims 1 to 3, wherein R ² represents trifluoromethyl; or a salt thereof. If the compound of claim 1, it is also a compound of formula (I _TA )

Where n represents the integer 1 or 2; R ^1A represents hydrogen, (C _1-4 ) alkyl, (C _3-6 ) cycloalkyl, (C _1-2 ) alkoxy-(C _1-2 ) alkyl , (C _1-2 )alkyl-carbonyl, hydroxy-(C _1-4 )alkyl, (C _1-2 )fluoroalkyl, phenyl or heteroaryl, wherein the heteroaryl contains 1, 2 Or 3 5 or 6 membered monocyclic aromatic rings independently selected from heteroatoms of oxygen, nitrogen and sulfur, and wherein the heteroaryl group is independently unsubstituted or monosubstituted by (C _1-4 ) alkyl; R ^1B represents hydrogen or (C _1-4 )alkyl; and R ² represents (C _3-6 )cycloalkyl, (C _1-4 )alkoxy or (C _1-2 )fluoroalkyl; or salt. The compound according to claim 5, wherein R ^1A represents (C _1-4 )alkyl, (C _3-6 )cycloalkyl, (C _1-2 )alkoxy-(C _1-2 )alkyl, hydroxyl -(C _1-4 ) alkyl or (C _1-2 ) fluoroalkyl; or a salt thereof. The compound according to claim 5, wherein R ^1A represents (C _1-4 )alkyl or (C _3-6 )cycloalkyl; or a salt thereof. The compound according to any one of claims 5 to 7, wherein R ^1B represents hydrogen; or a salt thereof. The compound according to any one of claims 5 to 7, wherein R ^1B represents a methyl group; or a salt thereof. The compound according to any one of claims 5 to 7, wherein R ² represents trifluoromethyl; or a salt thereof. The compound according to claim 8, wherein R ² represents trifluoromethyl; or a salt thereof. The compound as claimed in claim 1, which is selected from the group consisting of: 2-(3-tert-butyl-[1,2,4]triazol-1-yl)-1-{(S)-2-hydroxyl Methyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone; 2-(3,5-dimethyl-[1,2,4]triazol-1-yl)-1-{(S)-2-hydroxymethyl-4- [2-Trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone; 2-(3-cyclopropyl-[1,2,4]triazol-1-yl)-1-{(S)-2-hydroxymethyl-4-[2 -Trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone; 1-{(S)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazole -5-yl]-hexahydropyridine

-1-yl}-2-(3-isopropyl-[1,2,4]triazol-1-yl)-ethanone; 1-{(S)-2-hydroxymethyl-4-[2 -Trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-2-(3-trifluoromethyl-[1,2,4]triazol-1-yl)-ethanone; 1-{(S)-4-[4-(2-ethyl Oxy-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-hydroxymethyl-hexahydropyridine

-1-yl}-2-(3-trifluoromethyl-[1,2,4]triazol-1-yl)-ethanone; 2-(3,5-dimethyl-[1,2, 4]Triazol-1-yl)-1-{(S)-4-[4-(2-ethoxy-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]- 2-hydroxymethyl-hexahydropyridine

-1-yl}-ethanone; 1-{(S)-4-[4-(2-cyclopropyl-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2 -Hydroxymethyl-hexahydropyridine

-1-yl}-2-(3,5-dimethyl-[1,2,4]triazol-1-yl)-ethanone; 1-{(S)-4-[4-(2- Cyclopropyl-pyrimidin-5-yl)-2-trifluoromethyl-thiazol-5-yl]-2-hydroxymethyl-hexahydropyridine

-1-yl}-2-(3-trifluoromethyl-[1,2,4]triazol-1-yl)-ethanone; 1-{(R)-2-hydroxymethyl-4-[ 2-trifluoromethyl-4-(6-trifluoromethyl-pyridin-3-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-2-(3-isopropyl-[1,2,4]triazol-1-yl)-ethanone; 1-{(R)-2-hydroxymethyl-4-[2 -Trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-2-(3-isopropyl-[1,2,4]triazol-1-yl)-ethanone; 2-(3,5-dimethyl-[1,2,4 ]Triazol-1-yl)-1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazole -5-yl]-hexahydropyridine

-1-yl}-ethanone; 2-benzimidazol-1-yl-1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl -Pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone; 2-(5-fluoro-indol-1-yl)-1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl-4-( 2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone; 1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazole -5-yl]-hexahydropyridine

-1-yl}-2-(5-methoxy-indol-1-yl)-ethanone; 1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl-4 -(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone; 1-{(R)-2-hydroxymethyl-4-[2- Trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-2-(3-methoxymethyl-[1,2,4]triazol-1-yl)-ethanone; 1-{(R)-2-hydroxymethyl-4- [2-Trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-2-[3-(5-methyl-[1,2,4]oxadiazol-3-yl)-[1,2,4]triazol-1-yl]-ethanone ; 1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydro Pyridine

-1-yl}-2-(3-phenyl-[1,2,4]triazol-1-yl)-ethanone; 2-(3-acetoxy-[1,2,4]triazole -1-yl)-1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazole-5- Radical]-hexahydropyridine

-1-yl}-ethanone; 2-[3-(1-hydroxy-ethyl)-[1,2,4]triazol-1-yl]-1-{(R)-2-hydroxymethyl -4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone; 1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazole -5-yl]-hexahydropyridine

-1-yl}-2-(3-methyl-pyrazol-1-yl)-ethanone; 1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl-4- (2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-2-(3-pyridin-2-yl-[1,2,4]triazol-1-yl)-ethanone; 2-(3-ethyl-5-methyl-[1 ,2,4]triazol-1-yl)-1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidine-5- Group)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone; 2-(5-ethyl-3-methyl-[1,2,4]triazol-1-yl)-1-{(R)-2-hydroxymethyl- 4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone; 1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazole -5-yl]-hexahydropyridine

-1-yl}-2-imidazo[4,5-b]pyridin-3-yl-ethanone; 2-(3,5-dimethyl-[1,2,4]triazol-1-yl )-1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazole-5 -Yl]-hexahydropyridine

-1-yl}-ethanone; 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidine-5 -Yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-2-(3-trifluoromethyl-[1,2,4]triazol-1-yl)-ethanone; 2-(3-cyclobutyl-[1,2,4] Triazol-1-yl)-1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidine-5- Group)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone; 2-(3-tert-butyl-[1,2,4]triazol-1-yl)-1-{(R)-2-(2-hydroxy-ethyl )-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone; 2-(3-cyclopropyl-[1,2,4]triazol-1-yl)-1-{(R)-2-(2-hydroxy-ethyl) -4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone; 2-(3-ethyl-[1,2,4]triazol-1-yl)-1-{(R)-2-(2-hydroxy-ethyl)- 4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone; 2-(5-ethyl-[1,2,4]triazol-1-yl)-1-{(R)-2-(2-hydroxy-ethyl)- 4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone; 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidine-5 -Yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-2-(3-isopropyl-[1,2,4]triazol-1-yl)-ethanone; 1-{(R)-2-(2-hydroxy-ethyl) -4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone; 1-{(R)-2-(2-hydroxy-ethyl)- 4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-2-(5-methyl-[1,2,4]triazol-1-yl)-ethanone; 1-{(R)-2-(2-hydroxy-ethyl)- 4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-2-(3-methoxymethyl-[1,2,4]triazol-1-yl)-ethanone; and 2-(3-difluoromethyl-[1,2 ,4]triazol-1-yl)-1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl) -Thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone; or a salt thereof. The compound of claim 1, which is selected from the group consisting of: 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoro Methyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-2-(3-methyl-pyrazol-1-yl)-ethanone; 2-(3-ethyl-pyrazol-1-yl)-1-{(R)-2- (2-Hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone; 2-(3-cyclopropyl-pyrazol-1-yl)-1-{(R)-2-(2-hydroxy-ethyl)-4-[2-tri Fluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone; 1-{(S)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazole -5-yl]-hexahydropyridine

-1-yl}-2-(3-methyl-pyrazol-1-yl)-ethanone; 2-(3-ethyl-pyrazol-1-yl)-1-{(S)-2- Hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone; and 2-(3-cyclopropyl-pyrazol-1-yl)-1-{(S)-2-hydroxymethyl-4-[2-trifluoromethyl- 4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone; or a salt thereof. The compound according to claim 1, wherein the compound is 1-{(R)-2-hydroxymethyl-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl) -Thiazol-5-yl]-hexahydropyridine

-1-yl}-2-(3-methyl-pyrazol-1-yl)-ethanone; or a salt thereof. The compound according to claim 1, wherein the compound is 2-(3-ethyl-[1,2,4]triazol-1-yl)-1-{(R)-2-(2-hydroxy-ethyl )-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidin-5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-ethanone; or a salt thereof. The compound according to claim 1, wherein the compound is 1-{(R)-2-(2-hydroxy-ethyl)-4-[2-trifluoromethyl-4-(2-trifluoromethyl-pyrimidine -5-yl)-thiazol-5-yl]-hexahydropyridine

-1-yl}-2-(3-methyl-[1,2,4]triazol-1-yl)-ethanone; or a salt thereof. A pharmaceutical composition comprising as an active ingredient a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert excipient. The compound according to any one of claims 1 to 3, 5 to 7 and 12 to 16, or a pharmaceutically acceptable salt thereof, is used as a medicament. A compound as claimed in any one of claims 1 to 3, 5 to 7 and 12 to 16, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of diseases selected from the group consisting of: autoimmune disorders , Inflammatory diseases, infectious diseases, transplant rejection, fibrosis, neurodegenerative disorders and cancer. Use of a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof for the preparation of an agent for the prevention or treatment of a disease selected from the group consisting of: autoimmune disorders, Inflammatory diseases, infectious diseases, transplant rejection, fibrosis, neurodegenerative disorders and cancer. Use of a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention or treatment of a disease selected from the group consisting of rheumatoid arthritis , Inflammatory bowel disease, Crohn's disease, ulcerative colitis, systemic lupus erythematosus, lupus nephritis, interstitial cystitis, myasthenia gravis, type I diabetes, atherosclerosis, dry eye disease, Heart transplant rejection, kidney transplant rejection, graft-versus-host disease, and cirrhosis.